{"gene":"DLX2","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2006,"finding":"The noncoding RNA Evf-2, transcribed from the Dlx-5/6 ultraconserved region, forms a stable complex with DLX-2 protein in vivo and specifically cooperates with DLX-2 to increase transcriptional activity of the Dlx-5/6 enhancer in a target- and homeodomain-specific manner, identifying a mechanism whereby an ncRNA activates transcription by directly influencing homeodomain protein activity.","method":"In vivo co-immunoprecipitation (stable Evf-2/DLX-2 complex), reporter/transcription assays, RNA-protein interaction studies","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal in vivo complex formation plus functional reporter assays in a single focused study","pmids":["16705037"],"is_preprint":false},{"year":1995,"finding":"Null mutation of Dlx-2 in mice causes abnormal differentiation within the forebrain and respecification of a subset of cranial neural crest cells, leading to abnormal morphogenesis of skeletal elements derived from the proximal first and second branchial arches, demonstrating that Dlx-2 is required for branchial arch development and forebrain differentiation.","method":"Gene targeting (null mutation), histological and skeletal phenotype analysis in homozygous mutant mice","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with defined cellular phenotype, replicated across multiple subsequent studies","pmids":["7590232"],"is_preprint":false},{"year":1997,"finding":"Mice lacking both Dlx-1 and Dlx-2 show a time-dependent block in striatal differentiation: early born neurons migrate into a striatum-like region, but later born neurons accumulate in the proliferative zone, demonstrating that Dlx-1 and Dlx-2 are required for development of the striatal subventricular zone and differentiation of late-born striatal matrix neurons.","method":"Double knockout mouse, histological and marker analysis of striatal phenotype","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean double knockout with defined compartment-specific cellular phenotype, replicated in follow-up studies","pmids":["9247261"],"is_preprint":false},{"year":1997,"finding":"Dlx-1 and Dlx-2 double null mice fail to develop maxillary molar teeth; heterologous recombination experiments showed that Dlx-1/2 mutant ectomesenchyme loses odontogenic potential and its cells adopt a chondrogenic fate instead (marked by Barx1/Sox9 expression), demonstrating that Dlx-1 and Dlx-2 specify odontogenic identity in cranial neural crest-derived ectomesenchyme.","method":"Double knockout mouse, heterologous tissue recombination, molecular marker analysis (Barx1, Sox9)","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout plus tissue recombination with fate-marker evidence, multiple orthogonal approaches","pmids":["9428417"],"is_preprint":false},{"year":1997,"finding":"Antisense oligonucleotide blockade of Dlx-2 expression in primary basal ganglia cultures caused specific decreases in MAP2 expression and dendrite outgrowth, and increased cell proliferation, demonstrating that Dlx-2 regulates neuronal differentiation by promoting exit from the mitotic cycle and growth of MAP2-positive dendrites.","method":"Antisense oligonucleotide knockdown in primary cultures, MAP2 immunostaining, cell proliferation assays","journal":"Journal of molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — antisense knockdown in primary culture with two phenotypic readouts (dendrite morphology, proliferation), single lab","pmids":["9188040"],"is_preprint":false},{"year":1997,"finding":"Dlx-1 and Dlx-2 mutations disrupt proximodistal patterning of the branchial arches in a region-specific manner; single Dlx-1 mutants reveal distinct proximal skeletal and soft tissue defects, and Dlx-1/2 double mutants show unique additional abnormalities including absence of maxillary molars, establishing distinct and overlapping roles for Dlx-1 and Dlx-2 in craniofacial patterning.","method":"Single and double knockout mouse models, skeletal and soft tissue analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple clean knockout genotypes with defined skeletal phenotypes, replicated across labs","pmids":["9187081"],"is_preprint":false},{"year":2000,"finding":"Dlx2 epithelial expression in the first branchial arch is regulated by BMP4 (planar signaling), while mesenchymal expression is regulated by FGF8 from the overlying epithelium; FGF8 also inhibits Dlx2 epithelial expression via a mesenchyme-dependent signaling pathway. Transgenic reporter mapping of a 3.8 kb upstream Dlx2 sequence confirmed epithelial-specific regulatory elements.","method":"Transgenic reporter (lacZ) analysis, signaling factor treatment of explants, regulatory element mapping","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic reporter plus signaling perturbations, single lab, two orthogonal approaches","pmids":["10603340"],"is_preprint":false},{"year":2001,"finding":"BMP-2 stimulates Dlx-2 expression in chondroblasts, and antisense oligonucleotide blockade of Dlx-2 abolishes BMP-2-mediated transcriptional activation of the chondrocyte-specific Col2alpha1 enhancer; dominant-negative Smad1 similarly blocks BMP-2 signaling to Col2alpha1, establishing Dlx-2 as a downstream mediator of BMP-2/Smad signaling required for Col2alpha1 gene expression.","method":"Antisense oligonucleotide knockdown, dominant-negative Smad1, Col2alpha1 enhancer reporter assays","journal":"DNA and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antisense knockdown plus dominant-negative epistasis plus reporter assay, single lab","pmids":["11445007"],"is_preprint":false},{"year":2001,"finding":"PITX2 activates the Dlx2 promoter (~45-fold in CHO cells) by binding bicoid and bicoid-like elements in the Dlx2 promoter; Msx2 represses the Dlx2 promoter by competing with PITX2 for binding to the bicoid element; co-expression of PITX2 and Msx2 results in transcriptional antagonism at the Dlx2 promoter.","method":"Luciferase reporter assays, EMSA (electrophoretic mobility shift assay), RT-PCR, Western blot","journal":"Gene expression","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA plus reporter assays demonstrating direct binding and functional antagonism, single lab","pmids":["11763998"],"is_preprint":false},{"year":2004,"finding":"In the Dlx1/2 double null retina, late-born retinal ganglion cells (RGCs) are lost due to increased apoptosis and there is ectopic expression of Crx in the ganglion cell layer, while amacrine and horizontal cell differentiation is relatively unaffected, demonstrating that Dlx1 and Dlx2 are required for terminal differentiation and survival of late-born RGCs.","method":"Double knockout mouse, histological and marker analysis of retinal phenotype, TUNEL apoptosis assay","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean double knockout with cell-type-specific phenotype, ectopic marker expression as fate readout","pmids":["15604100"],"is_preprint":false},{"year":2005,"finding":"Ectopic expression of Dlx2 in the chick neural tube via electroporation dramatically inhibits neural crest cell migration, induces cell aggregation, and in branchial arch mesenchyme induces N-cadherin and NCAM expression and increases mesenchymal condensation, demonstrating that Dlx2 regulates ectomesenchymal cell adhesion.","method":"In ovo electroporation, immunostaining for N-cadherin and NCAM, cell migration assay","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function in ovo with defined adhesion molecule readouts, single lab","pmids":["15848386"],"is_preprint":false},{"year":2006,"finding":"Chromatin immunoprecipitation (ChIP) identified Msx2 as a direct downstream target of Dlx2; Dlx2 activates the Msx2 promoter and binds DNA as both monomer and dimer; LEF-1 physically interacts with Dlx2 (by co-immunoprecipitation and protein pull-down) and synergistically activates the Msx2 promoter with Dlx2; Msx2 can auto-regulate its own promoter and represses Dlx2-mediated activation in a dose-specific manner.","method":"ChIP, co-immunoprecipitation, protein pull-down, luciferase reporter assays, deletion analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ChIP plus reciprocal Co-IP/pulldown plus functional reporter, multiple orthogonal methods, single lab","pmids":["17068080"],"is_preprint":false},{"year":2007,"finding":"Dlx1 and Dlx2 transcription factors repress oligodendrocyte precursor cell (OPC) formation in the ventral telencephalon; progenitors from Dlx1/2 mutant ventral telencephalon transplanted into wild-type mice do not produce neurons but differentiate into myelinating oligodendrocytes that survive into adulthood, demonstrating that Dlx1&2 act on a common progenitor to determine neuronal versus oligodendroglial cell fate.","method":"Double knockout mouse, progenitor transplantation into wild-type host, myelination/marker analysis","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout plus transplantation rescue experiment with cell-fate readout, independent replicated finding","pmids":["17678855"],"is_preprint":false},{"year":2007,"finding":"DLX2 binds directly to a specific region of the TrkB promoter in retinal neuroepithelium (demonstrated by ChIP), activates TrkB transcription in vitro, and ectopic Dlx2 expression in retinal explants activates TrkB expression while Dlx2 knockdown in primary retinal cultures reduces TrkB expression, establishing TrkB as a direct transcriptional target of DLX2 in RGC differentiation.","method":"ChIP, luciferase reporter assay, ectopic expression in retinal explants, siRNA knockdown in primary cultures","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ChIP plus reporter plus gain- and loss-of-function in primary tissue, multiple orthogonal methods","pmids":["18086710"],"is_preprint":false},{"year":2008,"finding":"Dlx2 is necessary for neurogenesis of virtually all olfactory bulb interneurons arising from the lateral subependymal zone (SEZ) as shown by retroviral loss-of-function, and promotes specification of periglomerular neurons (PGNs) toward a dopaminergic fate; this PGN subtype specification requires interaction between Dlx2 and Pax6, as Pax6 deletion blocks Dlx2-mediated PGN specification.","method":"Retroviral cell-autonomous loss-of-function, genetic epistasis (Pax6 conditional knockout), immunostaining of neuronal subtypes","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-autonomous retroviral knockdown plus genetic epistasis, two orthogonal approaches in same study","pmids":["18562615"],"is_preprint":false},{"year":2008,"finding":"Dlx2 directly activates the Arx GABAergic enhancer: Dlx overexpression induces ectopic endogenous Arx expression, loss of Dlx expression reduces Arx expression, and Arx is necessary for Dlx-dependent promotion of interneuron migration but not for GABAergic cell fate commitment, establishing a direct genetic hierarchy between Dlx2 and Arx in telencephalic GABAergic neuron development.","method":"Gain-of-function (Dlx overexpression), loss-of-function (Dlx/Arx mutants), enhancer reporter assay, genetic epistasis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain- and loss-of-function combined with epistasis across multiple mutant backgrounds","pmids":["18923043"],"is_preprint":false},{"year":2008,"finding":"The Rb/E2F pathway directly regulates the Dlx1/Dlx2 bigene cluster: Rb deficiency dramatically reduces Dlx1 and Dlx2 expression; repressor E2Fs bind and inhibit transcription at the Dlx1/Dlx2 promoters and the I12b forebrain enhancer in vitro and in vivo (ChIP), establishing that the cell cycle machinery modulates neuronal differentiation and migration by direct repression of Dlx gene expression.","method":"Rb knockout mouse, ChIP, in vitro reporter assays, interneuron subtype and migration analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP plus knockout plus reporter, multiple orthogonal methods demonstrating direct regulatory relationship","pmids":["22699903"],"is_preprint":false},{"year":2008,"finding":"Both the I12b and URE2 cis-regulatory elements at the Dlx1/2 locus are direct transcriptional targets of DLX2 and require Dlx1 and Dlx2 expression for proper enhancer activity, as demonstrated by in vivo Cre-based fate mapping and Dlx1/2 mutant analysis.","method":"Cre-transgenic mice, fate mapping (Z/EG reporter), Dlx1/2 mutant analysis, enhancer activity assays","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo enhancer activity assay in Dlx mutant background, single lab","pmids":["19026749"],"is_preprint":false},{"year":2009,"finding":"DLX2 promotes lineage transition from neural stem cells (NSCs) to transit-amplifying precursors (TAPs) and enhances the proliferative response of neuronal progenitors to EGF, demonstrating that DLX2 and EGFR signaling interact at multiple steps to coordinate proliferation in the postnatal subventricular zone.","method":"Forced DLX2 expression in SVZ-isolated NSCs, in vitro proliferation and lineage assays, EGF response measurement","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined in vitro gain-of-function with lineage and proliferation readouts, single lab","pmids":["19683576"],"is_preprint":false},{"year":2011,"finding":"Dlx-2 is induced in cancer cells by glucose deprivation in a reactive oxygen species (ROS)-dependent manner; Dlx-2 shRNA prevents metabolic stress-induced increases in mitochondrial ROS and suppresses metabolic stress-induced necrosis (measured by PI-positive cells, HMGB1 and LDH release), demonstrating Dlx-2's role in regulating metabolic stress-induced necrosis.","method":"shRNA knockdown, propidium iodide staining, HMGB1/LDH release assay, mitochondrial ROS measurement","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA knockdown with multiple mechanistic readouts in cancer cell lines, single lab","pmids":["21917150"],"is_preprint":false},{"year":2011,"finding":"Dlx2 acts as a direct transcriptional repressor of TGFβ receptor II (TGFβRII) gene expression, thereby reducing canonical Smad-dependent TGFβ signaling, p21CIP1 expression, and increasing c-Myc expression; additionally, Dlx2 directly induces betacellulin expression to promote cell survival via EGF receptor signaling, thus counteracting TGFβ-induced cell-cycle arrest and apoptosis.","method":"Reporter assays, Western blot, gene expression analysis, overexpression/knockdown in mammary epithelial cells","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct repressor function demonstrated by reporter assays plus pathway marker analysis, single lab","pmids":["21897365"],"is_preprint":false},{"year":2015,"finding":"Dlx-2 induces epithelial-mesenchymal transition (EMT) and glycolytic switch by activating Snail expression; Dlx-2 is induced by TGF-β and Wnt, and mediates their induction of EMT, glycolytic switch, and suppression of cytochrome c oxidase (COX) subunit expression (including COXVIc) in a Snail-dependent manner.","method":"shRNA knockdown, gene expression analysis, Western blot, pathway perturbation with TGF-β/Wnt in cancer cell lines","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA knockdown plus signaling perturbations with defined downstream target readouts, single lab","pmids":["25651912"],"is_preprint":false},{"year":2016,"finding":"Dlx-2 induces expression of glutaminase (GLS1), a key glutamine metabolism enzyme; GLS1 shRNA, glutamine deprivation, and metabolism inhibitors prevent Dlx-2-, TGF-β-, Wnt-, and Snail-induced EMT and glycolytic switch; Dlx-2/GLS1 inhibition also decreases Snail mRNA through p53-dependent upregulation of Snail-targeting microRNAs.","method":"shRNA knockdown, pharmacological inhibitors, gene expression analysis, in vivo metastasis assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA plus pharmacological inhibition with multiple downstream readouts and in vivo validation, single lab","pmids":["26771232"],"is_preprint":false},{"year":2016,"finding":"DLX2 expression reduces protein components of the TTI1/TTI2/TEL2 complex (required for proper folding and stabilization of ATM and other PIKK kinases), leading to reduced ATM-p53 signaling and bypass of replicative senescence, as identified in a gain-of-function senescence bypass screen.","method":"Gain-of-function screen, protein complex component analysis, ATM-p53 signaling assays, replicative lifespan measurement","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional screen with mechanistic follow-up on TTI/TEL2 complex, single lab","pmids":["26833729"],"is_preprint":false},{"year":2016,"finding":"DLX2 expression is induced by ionizing radiation in a Smad2/3-dependent manner; DLX2 overexpression alone induces EMT, migration, invasion, and cancer stem cell marker expression; DLX2 depletion abolishes radiation-induced EMT and increases radiation sensitivity, demonstrating that DLX2 mediates radiation-induced EMT and radioresistance downstream of Smad2/3 signaling.","method":"siRNA knockdown, DLX2 overexpression, Smad2/3 knockdown, colony formation assay, migration/invasion assays in cancer cell lines","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic siRNA knockdown of Smad2/3 upstream plus DLX2 gain/loss of function, single lab","pmids":["26799321"],"is_preprint":false},{"year":2017,"finding":"BMP type I receptor ALK-2 mediates DLX2 induction in glioma-initiating cells; DLX2 promotes apoptosis and neural differentiation of glioma-initiating cells; valproic acid induces BMP2/BMP4/ACVR1/DLX2 expression with increased Smad1/5 phosphorylation, and silencing ALK-2 or DLX2 partially suppresses VPA-induced apoptosis, establishing DLX2 as a pro-apoptotic BMP target gene in glioblastoma.","method":"siRNA knockdown, VPA treatment, Smad phosphorylation analysis, orthotopic mouse transplantation model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA epistasis plus in vivo orthotopic model, single lab","pmids":["28459464"],"is_preprint":false},{"year":2017,"finding":"DLX1 and DLX2 function as direct transcriptional activators of Brn3b expression in retinal ganglion cells; Dlx2 knockdown in primary embryonic retinal cultures reduces Brn3b expression, and Dlx2 gain-of-function in utero is sufficient for Brn3b expression; triple Dlx1/Dlx2/Brn3b knockout retinas show near-total RGC loss with marked increase in amacrine cells, a more severe phenotype than either double or single knockouts.","method":"Triple knockout mouse, Dlx2 knockdown in primary cultures, in utero gain-of-function, marker and cell-fate analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (triple KO), gain- and loss-of-function with cell-fate readouts, multiple orthogonal approaches","pmids":["28356311"],"is_preprint":false},{"year":2018,"finding":"DLX2 directly drives Gad1, Gad2, and Vgat expression in cortical interneurons (demonstrated by conditional knockout evidence); Dlx1&2 conditional knockouts show reduced mIPSC amplitude, fewer GABAergic synapses on excitatory neurons, reduced mIPSC frequency, hypoplastic dendrites, fewer excitatory synapses, and reduced GRIN2B expression.","method":"Conditional knockout (Dlx1, Dlx2, Dlx1&2 CKOs), electrophysiology (mIPSC), immunostaining, gene expression analysis","journal":"Cerebral cortex","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple conditional knockouts with electrophysiological and molecular readouts, multiple orthogonal methods","pmids":["29028947"],"is_preprint":false},{"year":2019,"finding":"DLX2 directly binds to Dlx2-response cis-acting elements in the promoters of Osteocalcin (OCN) and Alp genes (demonstrated by ChIP and site-directed mutagenesis of the binding elements) and transactivates their expression, thereby promoting osteogenic differentiation of BMSCs and MC3T3-E1 cells without affecting Runx2, Dlx5, Msx2, or Osterix levels.","method":"ChIP assay, site-directed mutagenesis, luciferase reporter assay, ALP activity, Alizarin red staining, in vivo implantation in nude mice","journal":"International journal of oral science","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ChIP plus mutagenesis of binding sites plus functional reporter plus in vivo validation, multiple orthogonal methods","pmids":["30880332"],"is_preprint":false},{"year":2020,"finding":"DLX2 acts as a transcription factor for WNT1, directly binding the WNT1 promoter (confirmed by ChIP), activating Wnt/β-catenin signaling to promote osteogenic differentiation of hBMSCs; inhibition of β-catenin by FH535 restrains DLX2-enhanced osteogenic differentiation.","method":"ChIP assay, reporter assay (implied), Western blot, ALP activity, Alizarin red staining, β-catenin inhibitor rescue","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus pharmacological epistasis with functional osteogenic readouts, single lab","pmids":["32165291"],"is_preprint":false},{"year":2021,"finding":"Misexpression of Dlx2 alone in postnatal mouse oligodendrocyte precursor cells (OPCs) is sufficient to switch their fate to GABAergic neurons within 2 days by downregulating Olig2 and upregulating a network of inhibitory neuron transcripts; after two weeks some OPC-derived neurons generate action potentials and form clusters of GABAergic synaptic proteins.","method":"Dlx2 misexpression in OPCs, transcriptome analysis, electrophysiology, immunostaining of synaptic markers","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function with defined molecular (Olig2/Dlx2 switch) and functional (electrophysiology) readouts, single lab with multiple orthogonal methods","pmids":["33574458"],"is_preprint":false},{"year":2018,"finding":"Dlx2 overexpression in chondroblasts increases accumulation of aggrecan and type II collagen by directly repressing MMP13 expression; luciferase reporter and ChIP analysis demonstrated that Dlx2 inhibits MMP13 expression by directly binding to two Dlx2-response elements in the MMP13 promoter.","method":"Dlx2 overexpression, luciferase reporter assay, ChIP, Western blot, qRT-PCR","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ChIP plus mutagenesis-based reporter plus protein-level readouts, multiple orthogonal methods, single lab","pmids":["29787757"],"is_preprint":false},{"year":2023,"finding":"JMJD3 demethylase promotes DLX2 expression by inhibiting H3K27me3 modification at the DLX2 locus; JMJD3 depletion phenocopies DLX2 loss (suppressed vascular smooth muscle cell proliferation, promoted apoptosis), and DLX2 overexpression rescues the effects of JMJD3 knockdown, demonstrating an epigenetic regulatory axis controlling DLX2 in intracranial aneurysm.","method":"siRNA knockdown of JMJD3 and DLX2, H3K27me3 chromatin analysis, rescue overexpression, in vivo model","journal":"The Tohoku journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic knockdown/rescue with epigenetic mark analysis, single lab","pmids":["37286519"],"is_preprint":false},{"year":2026,"finding":"DLX2 acts as a pioneer factor by forming a complex with LAP2α (lamina-associated polypeptide 2, isoform alpha) through a 38-amino-acid homeodomain motif, interacting with nucleosomes to promote chromatin remodeling and activate a procraniofacial ectomesenchymal gene network; disrupting DLX2-LAP2α interaction or silencing Dlx2 targets markedly diminished ectomesenchymal differentiation of murine ESCs.","method":"ESC differentiation assay, co-immunoprecipitation (DLX2-LAP2α complex), domain mutagenesis, chromatin remodeling assays, scRNA-seq trajectory analysis","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — complex formation by Co-IP plus domain mutagenesis plus functional differentiation assay, multiple orthogonal methods in single study","pmids":["41533791"],"is_preprint":false},{"year":2025,"finding":"DLX2 directly represses Notch signaling genes and glial fate-promoting transcription factors in ventral telencephalon progenitors, as revealed by single-cell multi-omic analysis; DLX2 maintains progenitor populations in a secondary proliferative zone of the ventral subventricular zone and facilitates neural differentiation by spatiotemporal-context-dependent Notch pathway repression.","method":"Single-cell whole genome spatial transcriptomics, multi-omic approach, DLX2 regulatory network analysis in ventral telencephalon","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multi-omic single-cell profiling with direct regulatory network evidence but preprint, single lab","pmids":[],"is_preprint":true},{"year":2022,"finding":"TAF15 physically interacts with lncRNA HOTTIP and stabilizes DLX2 protein (demonstrated by RNA immunoprecipitation and RNA pulldown), and this HOTTIP-TAF15-DLX2 axis promotes osteogenic differentiation and angiogenesis in hBMSCs.","method":"RNA immunoprecipitation (RIP), RNA pulldown, Western blot, ALP activity, Alizarin red staining","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RIP and RNA pulldown demonstrating TAF15-HOTTIP interaction with DLX2 stabilization as functional readout, single lab","pmids":["35644412"],"is_preprint":false}],"current_model":"DLX2 is a homeodomain transcription factor that acts as a pioneer factor forming complexes with partners including LAP2α (to remodel chromatin) and Evf-2 ncRNA (to enhance Dlx-5/6 transcription), directly activates targets such as Arx, Brn3b, TrkB, Gad1/2/Vgat, Osteocalcin, Alp, Wnt1, and MMP13 (or represses TGFβRII and Notch signaling genes), and is regulated upstream by BMP-2/Smad, FGF8, BMP4, Rb/E2F, and JMJD3-H3K27me3; it is required for striatal neuron differentiation, GABAergic interneuron specification and migration, neuronal versus oligodendroglial fate determination, retinal ganglion cell survival, olfactory bulb periglomerular neuron subtype specification (in cooperation with Pax6), craniofacial branchial arch patterning, odontogenic specification, and osteogenic/chondrogenic differentiation, while in cancer contexts it counteracts TGFβ-induced growth arrest, drives EMT via Snail/glutaminase, and bypasses senescence by destabilizing the ATM-activating TTI/TEL2 complex."},"narrative":{"mechanistic_narrative":"DLX2 is a homeodomain transcription factor that governs cell-fate specification and differentiation in neural, craniofacial, and skeletal lineages, and is redeployed in cancer to drive metabolic and epithelial-mesenchymal reprogramming [PMID:7590232, PMID:9247261, PMID:25651912]. In the forebrain, DLX2 (largely redundantly with DLX1) is required for striatal subventricular zone development and differentiation of late-born matrix neurons [PMID:9247261], for GABAergic interneuron specification and migration, and for the neuronal-versus-oligodendroglial fate decision in ventral telencephalic progenitors, where loss of Dlx1/2 reroutes progenitors to a myelinating oligodendrocyte fate [PMID:17678855]. It enforces these programs through a defined transcriptional hierarchy: DLX2 directly activates the Arx GABAergic enhancer to drive interneuron migration [PMID:18923043] and directly induces Gad1, Gad2, and Vgat to confer GABAergic synaptic identity [PMID:29028947], and its forced expression alone is sufficient to convert oligodendrocyte precursors into functional GABAergic neurons by repressing Olig2 [PMID:33574458]. In the retina, DLX1/2 directly activate Brn3b and TrkB to support terminal differentiation and survival of late-born retinal ganglion cells [PMID:18086710, PMID:28356311]. DLX2 also specifies odontogenic identity in cranial neural crest-derived ectomesenchyme and patterns the branchial arches, acting in part as a pioneer factor that binds nucleosomes via a homeodomain motif and partners with LAP2alpha to remodel chromatin and activate a procraniofacial gene network [PMID:7590232, PMID:9428417, PMID:41533791]. In osteogenic and chondrogenic contexts it directly transactivates Osteocalcin, Alp, and Wnt1 while repressing MMP13 [PMID:30880332, PMID:32165291, PMID:29787757]. Its expression is set by upstream signaling and chromatin inputs including BMP/Smad, FGF8, PITX2/Msx2 antagonism, Rb/E2F repression, and JMJD3-mediated H3K27me3 demethylation [PMID:10603340, PMID:11763998, PMID:22699903, PMID:37286519]. In cancer, DLX2 counteracts TGFbeta-induced growth arrest by directly repressing TGFbeta receptor II [PMID:21897365], drives EMT and a glycolytic switch through Snail and glutaminase (GLS1) [PMID:25651912, PMID:26771232], and bypasses replicative senescence by destabilizing the TTI1/TTI2/TEL2 complex to attenuate ATM-p53 signaling [PMID:26833729].","teleology":[{"year":1995,"claim":"Established that Dlx2 is genetically required in vivo, defining its essential roles in forebrain differentiation and branchial arch morphogenesis before any molecular target was known.","evidence":"Null-mutant mouse with histological and skeletal phenotyping","pmids":["7590232"],"confidence":"High","gaps":["Direct transcriptional targets not identified","Did not distinguish cell-autonomous from non-autonomous effects"]},{"year":1997,"claim":"Defined the developmental scope of Dlx1/Dlx2 by showing distinct and overlapping requirements in striatal neuron differentiation, odontogenic ectomesenchyme identity, and proximodistal arch patterning, establishing functional redundancy within the bigene cluster.","evidence":"Single and double knockout mice, tissue recombination, fate-marker analysis, antisense knockdown in primary cultures","pmids":["9247261","9428417","9187081","9188040"],"confidence":"High","gaps":["Mechanism of redundancy with Dlx1 not resolved at the molecular level","No direct target genes defined"]},{"year":2000,"claim":"Placed Dlx2 downstream of epithelial-mesenchymal signaling by showing BMP4 and FGF8 differentially control its tissue-specific expression in the first branchial arch.","evidence":"Transgenic lacZ reporter mapping plus signaling-factor treatment of explants","pmids":["10603340"],"confidence":"Medium","gaps":["Direct vs indirect transcriptional inputs not separated","Regulatory elements mapped only coarsely"]},{"year":2001,"claim":"Identified upstream transcriptional regulators of Dlx2, with BMP-2/Smad1 driving its expression in chondroblasts and PITX2/Msx2 acting as competing activator/repressor at the Dlx2 promoter.","evidence":"Antisense knockdown, dominant-negative Smad1, EMSA and luciferase reporter assays","pmids":["11445007","11763998"],"confidence":"Medium","gaps":["Endogenous occupancy of the bicoid elements not shown by ChIP","In vivo relevance of PITX2/Msx2 antagonism untested"]},{"year":2004,"claim":"Extended Dlx1/2 requirement to the retina, showing they are needed for terminal differentiation and survival of late-born retinal ganglion cells.","evidence":"Double knockout mouse with marker analysis and TUNEL apoptosis assay","pmids":["15604100"],"confidence":"High","gaps":["Direct targets in RGCs not yet identified","Cause of ectopic Crx expression unresolved"]},{"year":2005,"claim":"Linked Dlx2 to cell adhesion, showing gain-of-function induces N-cadherin/NCAM and mesenchymal condensation while blocking neural crest migration.","evidence":"In ovo electroporation with adhesion-molecule immunostaining and migration assays","pmids":["15848386"],"confidence":"Medium","gaps":["Adhesion genes not shown to be direct targets","Mechanism of migration arrest unknown"]},{"year":2006,"claim":"Revealed a non-protein partner mechanism: the ncRNA Evf-2 forms a stable complex with DLX-2 and cooperatively boosts Dlx-5/6 enhancer activity, showing ncRNAs can directly modulate homeodomain factor activity.","evidence":"In vivo co-immunoprecipitation and reporter/transcription assays","pmids":["16705037"],"confidence":"High","gaps":["Structural basis of Evf-2/DLX-2 binding unknown","Generality to other Dlx targets untested"]},{"year":2007,"claim":"Provided the first direct DNA targets and a protein cofactor: DLX2 binds and activates the TrkB and Msx2 promoters, dimerizes on DNA, and synergizes with LEF-1, while also repressing oligodendrocyte fate to control the neuron-vs-glia decision.","evidence":"ChIP, reciprocal Co-IP/pulldown, reporter assays, knockout plus progenitor transplantation","pmids":["18086710","17068080","17678855"],"confidence":"High","gaps":["Genome-wide target set not defined","How DLX2 switches between activation and repression unclear"]},{"year":2008,"claim":"Built the GABAergic transcriptional hierarchy and its upstream control, showing DLX2 directly activates the Arx enhancer and its own I12b/URE2 elements, cooperates with Pax6 for periglomerular dopaminergic fate, and is directly repressed by Rb/E2F.","evidence":"Gain/loss-of-function, enhancer reporter assays, retroviral loss-of-function, genetic epistasis, ChIP, Rb knockout","pmids":["18923043","18562615","19026749","22699903"],"confidence":"High","gaps":["Arx separates migration from fate commitment but the fate-commitment effector is unidentified","Coupling of cell cycle exit to differentiation not fully mechanistic"]},{"year":2009,"claim":"Connected DLX2 to progenitor proliferation, showing it drives the NSC-to-transit-amplifying-precursor transition and synergizes with EGFR signaling in the postnatal SVZ.","evidence":"Forced expression in SVZ NSCs with in vitro lineage and proliferation assays","pmids":["19683576"],"confidence":"Medium","gaps":["Direct transcriptional targets in proliferation control unknown","In vivo requirement not established here"]},{"year":2011,"claim":"Reframed DLX2 as an oncogenic effector, showing it directly represses TGFbetaRII to evade growth arrest and is induced by metabolic stress to regulate ROS-dependent necrosis in cancer cells.","evidence":"Reporter assays, overexpression/knockdown in mammary epithelial cells, shRNA with necrosis and mitochondrial ROS readouts","pmids":["21897365","21917150"],"confidence":"Medium","gaps":["Direct binding to TGFbetaRII promoter shown only by reporter assays","Mechanism of ROS-dependent induction undefined"]},{"year":2015,"claim":"Defined the EMT/metabolic program downstream of DLX2, showing it is induced by TGFbeta and Wnt and drives EMT and glycolytic switch via Snail and the metabolic enzyme glutaminase.","evidence":"shRNA knockdown, pathway perturbations, in vivo metastasis assay","pmids":["25651912","26771232"],"confidence":"Medium","gaps":["Snail and GLS1 not shown to be direct DLX2 transcriptional targets","Cancer-type generality untested"]},{"year":2016,"claim":"Established context-dependent dual roles in transformation: DLX2 mediates Smad2/3-driven radiation-induced EMT and radioresistance and bypasses senescence by destabilizing the TTI/TEL2 complex and ATM-p53 signaling, yet acts pro-apoptotically downstream of BMP/ALK-2 in glioma cells.","evidence":"Gain-of-function senescence screen, siRNA epistasis, ATM-p53 assays, orthotopic mouse model","pmids":["26799321","26833729","28459464"],"confidence":"Medium","gaps":["Basis for opposite pro-apoptotic vs pro-survival outputs unresolved","Mechanism of TTI/TEL2 destabilization not defined"]},{"year":2019,"claim":"Consolidated DLX2 as a direct osteo/chondrogenic regulator, showing it binds and transactivates Osteocalcin, Alp, and Wnt1 while directly repressing MMP13, with Wnt/beta-catenin as a key downstream axis.","evidence":"ChIP, site-directed mutagenesis, reporter assays, ALP/Alizarin red staining, in vivo implantation, beta-catenin inhibitor rescue","pmids":["30880332","32165291","29787757"],"confidence":"High","gaps":["Interplay with canonical osteogenic factors (Runx2/Osterix) left unaffected and unexplained","Coordination of activator vs repressor target selection unknown"]},{"year":2023,"claim":"Identified an epigenetic upstream control, with JMJD3 demethylase removing H3K27me3 at the DLX2 locus to permit its expression in vascular smooth muscle cells.","evidence":"siRNA knockdown/rescue, H3K27me3 chromatin analysis, in vivo aneurysm model","pmids":["37286519"],"confidence":"Medium","gaps":["Direct recruitment of JMJD3 to the locus not shown","Relevance beyond the aneurysm context unclear"]},{"year":2026,"claim":"Defined DLX2's molecular mode of action as a pioneer factor, showing it engages nucleosomes through a homeodomain motif and partners with LAP2alpha to remodel chromatin and activate a procraniofacial ectomesenchymal gene network.","evidence":"ESC differentiation, Co-IP, domain mutagenesis, chromatin remodeling assays, scRNA-seq trajectory analysis","pmids":["41533791"],"confidence":"High","gaps":["Genome-wide pioneering target catalogue not defined","Whether LAP2alpha partnership operates in non-craniofacial DLX2 functions unknown"]},{"year":null,"claim":"It remains unresolved how DLX2 selects between transcriptional activation and repression and between pro-differentiation and oncogenic outputs across tissues, and how its pioneer-factor activity and cofactor choice (LAP2alpha, LEF-1, Evf-2, Pax6) are coordinated genome-wide.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking activator vs repressor target choice","No genome-wide pioneer-binding map across cell types","Context-dependent pro-apoptotic vs pro-survival switch unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[11,13,15,20,28,31]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[11,13,28,29,31]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[11,13,28,33]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[11,13,15,28,31]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,2,3,12,26]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[33,32]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[20,29,25]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[21,22,23,24]}],"complexes":[],"partners":["LAP2ALPHA","LEF-1","EVF-2","PAX6","TAF15"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q07687","full_name":"Homeobox protein DLX-2","aliases":[],"length_aa":328,"mass_kda":34.2,"function":"Acts as a transcriptional activator (By similarity). Activates transcription of CGA/alpha-GSU, via binding to the downstream activin regulatory element (DARE) in the gene promoter (By similarity). Plays a role in terminal differentiation of interneurons, such as amacrine and bipolar cells in the developing retina. Likely to play a regulatory role in the development of the ventral forebrain (By similarity). May play a role in craniofacial patterning and morphogenesis (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q07687/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DLX2","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DLX2","total_profiled":1310},"omim":[{"mim_id":"620809","title":"ACHAETE-SCUTE FAMILY bHLH TRANSCRIPTION FACTOR 5; ASCL5","url":"https://www.omim.org/entry/620809"},{"mim_id":"620675","title":"LEUKODYSTROPHY, HYPOMYELINATING, 27; HLD27","url":"https://www.omim.org/entry/620675"},{"mim_id":"617479","title":"SSU2 HOMOLOG; SSUH2","url":"https://www.omim.org/entry/617479"},{"mim_id":"616404","title":"POLYMERASE I, RNA, SUBUNIT A; POLR1A","url":"https://www.omim.org/entry/616404"},{"mim_id":"608874","title":"OROFACIAL CLEFT 5; OFC5","url":"https://www.omim.org/entry/608874"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear speckles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"brain","ntpm":2.9}],"url":"https://www.proteinatlas.org/search/DLX2"},"hgnc":{"alias_symbol":["TES-1"],"prev_symbol":[]},"alphafold":{"accession":"Q07687","domains":[{"cath_id":"1.10.10.60","chopping":"157-210","consensus_level":"high","plddt":97.8015,"start":157,"end":210}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q07687","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q07687-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q07687-F1-predicted_aligned_error_v6.png","plddt_mean":58.47},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DLX2","jax_strain_url":"https://www.jax.org/strain/search?query=DLX2"},"sequence":{"accession":"Q07687","fasta_url":"https://rest.uniprot.org/uniprotkb/Q07687.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q07687/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q07687"}},"corpus_meta":[{"pmid":"10906711","id":"PMC_10906711","title":"Pallial and subpallial derivatives in the embryonic chick and mouse telencephalon, traced by the expression of the genes Dlx-2, Emx-1, Nkx-2.1, Pax-6, and Tbr-1.","date":"2000","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/10906711","citation_count":760,"is_preprint":false},{"pmid":"16705037","id":"PMC_16705037","title":"The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator.","date":"2006","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/16705037","citation_count":574,"is_preprint":false},{"pmid":"7687285","id":"PMC_7687285","title":"Spatially restricted expression of Dlx-1, Dlx-2 (Tes-1), Gbx-2, and Wnt-3 in the embryonic day 12.5 mouse forebrain defines potential transverse and longitudinal segmental boundaries.","date":"1993","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/7687285","citation_count":523,"is_preprint":false},{"pmid":"9247261","id":"PMC_9247261","title":"Mutations of the homeobox genes Dlx-1 and Dlx-2 disrupt the striatal subventricular zone and differentiation of late born striatal neurons.","date":"1997","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/9247261","citation_count":443,"is_preprint":false},{"pmid":"9187081","id":"PMC_9187081","title":"Role of the Dlx homeobox genes in proximodistal patterning of the branchial arches: mutations of Dlx-1, Dlx-2, and Dlx-1 and -2 alter morphogenesis of proximal skeletal and soft tissue structures derived from the first and second arches.","date":"1997","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/9187081","citation_count":389,"is_preprint":false},{"pmid":"7590232","id":"PMC_7590232","title":"Null mutation of Dlx-2 results in abnormal morphogenesis of proximal first and second branchial arch derivatives and abnormal differentiation in the forebrain.","date":"1995","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/7590232","citation_count":321,"is_preprint":false},{"pmid":"17678855","id":"PMC_17678855","title":"Dlx1 and Dlx2 control neuronal versus oligodendroglial cell fate acquisition in the developing forebrain.","date":"2007","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/17678855","citation_count":294,"is_preprint":false},{"pmid":"10516593","id":"PMC_10516593","title":"DLX-1, DLX-2, and DLX-5 expression define distinct stages of basal forebrain differentiation.","date":"1999","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/10516593","citation_count":237,"is_preprint":false},{"pmid":"7893603","id":"PMC_7893603","title":"Differential and overlapping expression domains of Dlx-2 and Dlx-3 suggest distinct roles for Distal-less homeobox genes in craniofacial development.","date":"1994","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/7893603","citation_count":217,"is_preprint":false},{"pmid":"9428417","id":"PMC_9428417","title":"Role of Dlx-1 and Dlx-2 genes in patterning of the murine dentition.","date":"1997","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/9428417","citation_count":198,"is_preprint":false},{"pmid":"8098616","id":"PMC_8098616","title":"The mouse Dlx-2 (Tes-1) gene is expressed in spatially restricted domains of the forebrain, face and limbs in midgestation mouse embryos.","date":"1993","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/8098616","citation_count":194,"is_preprint":false},{"pmid":"7965042","id":"PMC_7965042","title":"DLX-2, MASH-1, and MAP-2 expression and bromodeoxyuridine incorporation define molecularly distinct cell populations in the embryonic mouse forebrain.","date":"1994","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/7965042","citation_count":185,"is_preprint":false},{"pmid":"18562615","id":"PMC_18562615","title":"A dlx2- and pax6-dependent transcriptional code for periglomerular neuron specification in the adult olfactory bulb.","date":"2008","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/18562615","citation_count":164,"is_preprint":false},{"pmid":"18923043","id":"PMC_18923043","title":"Arx is a direct target of Dlx2 and thereby contributes to the tangential migration of GABAergic interneurons.","date":"2008","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/18923043","citation_count":120,"is_preprint":false},{"pmid":"12427838","id":"PMC_12427838","title":"Subpallial dlx2-expressing cells give rise to astrocytes and oligodendrocytes in the cerebral cortex and white matter.","date":"2002","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/12427838","citation_count":93,"is_preprint":false},{"pmid":"19026749","id":"PMC_19026749","title":"Generation of Cre-transgenic mice using Dlx1/Dlx2 enhancers and their characterization in GABAergic interneurons.","date":"2008","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/19026749","citation_count":90,"is_preprint":false},{"pmid":"10603340","id":"PMC_10603340","title":"Independent regulation of Dlx2 expression in the epithelium and mesenchyme of the first branchial arch.","date":"2000","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/10603340","citation_count":87,"is_preprint":false},{"pmid":"17494687","id":"PMC_17494687","title":"Distinct cis-regulatory elements from the Dlx1/Dlx2 locus mark different progenitor cell populations in the ganglionic eminences and different subtypes of adult cortical interneurons.","date":"2007","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/17494687","citation_count":87,"is_preprint":false},{"pmid":"29028947","id":"PMC_29028947","title":"Dlx1 and Dlx2 Promote Interneuron GABA Synthesis, Synaptogenesis, and Dendritogenesis.","date":"2018","source":"Cerebral cortex (New York, N.Y. : 1991)","url":"https://pubmed.ncbi.nlm.nih.gov/29028947","citation_count":73,"is_preprint":false},{"pmid":"30880332","id":"PMC_30880332","title":"Overexpression of Dlx2 enhances osteogenic differentiation of BMSCs and MC3T3-E1 cells via direct upregulation of Osteocalcin and Alp.","date":"2019","source":"International journal of oral science","url":"https://pubmed.ncbi.nlm.nih.gov/30880332","citation_count":73,"is_preprint":false},{"pmid":"8812481","id":"PMC_8812481","title":"Sequence, organization, and transcription of the Dlx-1 and Dlx-2 locus.","date":"1996","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8812481","citation_count":71,"is_preprint":false},{"pmid":"26771232","id":"PMC_26771232","title":"Dlx-2 and glutaminase upregulate epithelial-mesenchymal transition and glycolytic switch.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26771232","citation_count":68,"is_preprint":false},{"pmid":"15604100","id":"PMC_15604100","title":"Dlx1 and Dlx2 function is necessary for terminal differentiation and survival of late-born retinal ganglion cells in the developing mouse retina.","date":"2004","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/15604100","citation_count":67,"is_preprint":false},{"pmid":"11763998","id":"PMC_11763998","title":"Antagonistic regulation of Dlx2 expression by PITX2 and Msx2: implications for tooth development.","date":"2001","source":"Gene expression","url":"https://pubmed.ncbi.nlm.nih.gov/11763998","citation_count":62,"is_preprint":false},{"pmid":"21897365","id":"PMC_21897365","title":"Transcription factor Dlx2 protects from TGFβ-induced cell-cycle arrest and apoptosis.","date":"2011","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/21897365","citation_count":55,"is_preprint":false},{"pmid":"11180958","id":"PMC_11180958","title":"A zebrafish forebrain-specific zinc finger gene can induce ectopic dlx2 and dlx6 expression.","date":"2001","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/11180958","citation_count":43,"is_preprint":false},{"pmid":"11445007","id":"PMC_11445007","title":"Bone morphogenetic protein-2 (BMP-2) signaling to the Col2alpha1 gene in chondroblasts requires the homeobox gene Dlx-2.","date":"2001","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11445007","citation_count":43,"is_preprint":false},{"pmid":"7869122","id":"PMC_7869122","title":"Regionalization of the developing forebrain: a comparison of FORSE-1, Dlx-2, and BF-1.","date":"1995","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/7869122","citation_count":42,"is_preprint":false},{"pmid":"22699903","id":"PMC_22699903","title":"The Rb/E2F pathway modulates neurogenesis through direct regulation of the Dlx1/Dlx2 bigene cluster.","date":"2012","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/22699903","citation_count":41,"is_preprint":false},{"pmid":"15210202","id":"PMC_15210202","title":"Cloning and developmental expression patterns of Dlx2, Lhx7 and Lhx9 in the medaka fish (Oryzias latipes).","date":"2004","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/15210202","citation_count":41,"is_preprint":false},{"pmid":"21108812","id":"PMC_21108812","title":"Mutually exclusive expression of DLX2 and DLX5/6 is associated with the metastatic potential of the human breast cancer cell line MDA-MB-231.","date":"2010","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21108812","citation_count":40,"is_preprint":false},{"pmid":"29242628","id":"PMC_29242628","title":"Mutant Runx2 regulates amelogenesis and osteogenesis through a miR-185-5p-Dlx2 axis.","date":"2017","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/29242628","citation_count":40,"is_preprint":false},{"pmid":"19683576","id":"PMC_19683576","title":"Interaction between DLX2 and EGFR regulates proliferation and neurogenesis of SVZ precursors.","date":"2009","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/19683576","citation_count":39,"is_preprint":false},{"pmid":"12902388","id":"PMC_12902388","title":"Dlx2 progenitor migration in wild type and Nkx2.1 mutant telencephalon.","date":"2003","source":"Cerebral cortex (New York, N.Y. : 1991)","url":"https://pubmed.ncbi.nlm.nih.gov/12902388","citation_count":39,"is_preprint":false},{"pmid":"27336609","id":"PMC_27336609","title":"KI67 and DLX2 predict increased risk of metastasis formation in prostate cancer-a targeted molecular approach.","date":"2016","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/27336609","citation_count":37,"is_preprint":false},{"pmid":"31920462","id":"PMC_31920462","title":"Long non-coding RNA TUG1 promotes cell progression in hepatocellular carcinoma via regulating miR-216b-5p/DLX2 axis.","date":"2020","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/31920462","citation_count":36,"is_preprint":false},{"pmid":"1354641","id":"PMC_1354641","title":"DLX2 (TES1), a homeobox gene of the Distal-less family, assigned to conserved regions on human and mouse chromosomes 2.","date":"1992","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/1354641","citation_count":35,"is_preprint":false},{"pmid":"32065989","id":"PMC_32065989","title":"ASCL1- and DLX2-induced GABAergic neurons from hiPSC-derived NPCs.","date":"2020","source":"Journal of neuroscience methods","url":"https://pubmed.ncbi.nlm.nih.gov/32065989","citation_count":34,"is_preprint":false},{"pmid":"16964386","id":"PMC_16964386","title":"OY-TES-1 expression and serum immunoreactivity in epithelial ovarian cancer.","date":"2006","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/16964386","citation_count":34,"is_preprint":false},{"pmid":"22371698","id":"PMC_22371698","title":"Dynamic expression of the pro-dopaminergic transcription factors Pax6 and Dlx2 during postnatal olfactory bulb neurogenesis.","date":"2012","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/22371698","citation_count":34,"is_preprint":false},{"pmid":"25651912","id":"PMC_25651912","title":"Dlx-2 is implicated in TGF-β- and Wnt-induced epithelial-mesenchymal, glycolytic switch, and mitochondrial repression by Snail activation.","date":"2015","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/25651912","citation_count":34,"is_preprint":false},{"pmid":"28459464","id":"PMC_28459464","title":"Bone morphogenetic protein signaling mediated by ALK-2 and DLX2 regulates apoptosis in glioma-initiating cells.","date":"2017","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/28459464","citation_count":33,"is_preprint":false},{"pmid":"10750557","id":"PMC_10750557","title":"Biomineralization, life-time of odontogenic cells and differential expression of the two homeobox genes MSX-1 and DLX-2 in transgenic mice.","date":"2000","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/10750557","citation_count":32,"is_preprint":false},{"pmid":"28356311","id":"PMC_28356311","title":"Regulation of Brn3b by DLX1 and DLX2 is required for retinal ganglion cell differentiation in the vertebrate retina.","date":"2017","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/28356311","citation_count":28,"is_preprint":false},{"pmid":"15848386","id":"PMC_15848386","title":"Dlx2 over-expression regulates cell adhesion and mesenchymal condensation in ectomesenchyme.","date":"2005","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/15848386","citation_count":28,"is_preprint":false},{"pmid":"7554927","id":"PMC_7554927","title":"The spatial localization of Dlx-2 during tooth development.","date":"1995","source":"Connective tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/7554927","citation_count":28,"is_preprint":false},{"pmid":"26799321","id":"PMC_26799321","title":"Smad2/3-Regulated Expression of DLX2 Is Associated with Radiation-Induced Epithelial-Mesenchymal Transition and Radioresistance of A549 and MDA-MB-231 Human Cancer Cell Lines.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26799321","citation_count":27,"is_preprint":false},{"pmid":"17068080","id":"PMC_17068080","title":"Functional interactions between Dlx2 and lymphoid enhancer factor regulate Msx2.","date":"2006","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/17068080","citation_count":26,"is_preprint":false},{"pmid":"12722102","id":"PMC_12722102","title":"Dlx-1 and Dlx-2 expression in the adult mouse brain: relationship to dopaminergic phenotypic regulation.","date":"2003","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/12722102","citation_count":26,"is_preprint":false},{"pmid":"23674878","id":"PMC_23674878","title":"Increased expression of DLX2 correlates with advanced stage of gastric adenocarcinoma.","date":"2013","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/23674878","citation_count":26,"is_preprint":false},{"pmid":"20883215","id":"PMC_20883215","title":"Role of Dlx genes in craniofacial morphogenesis: Dlx2 influences skeletal patterning by inducing ectomesenchymal aggregation in ovo.","date":"2010","source":"Evolution & development","url":"https://pubmed.ncbi.nlm.nih.gov/20883215","citation_count":25,"is_preprint":false},{"pmid":"32977948","id":"PMC_32977948","title":"Knockdown of circ_HIPK3 inhibits tumorigenesis of hepatocellular carcinoma via the miR-582-3p/DLX2 axis.","date":"2020","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/32977948","citation_count":23,"is_preprint":false},{"pmid":"21917150","id":"PMC_21917150","title":"Homeobox gene Dlx-2 is implicated in metabolic stress-induced necrosis.","date":"2011","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21917150","citation_count":23,"is_preprint":false},{"pmid":"23246068","id":"PMC_23246068","title":"The effect of overexpression of Dlx2 on the migration, proliferation and osteogenic differentiation of cranial neural crest stem cells.","date":"2012","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/23246068","citation_count":22,"is_preprint":false},{"pmid":"26833729","id":"PMC_26833729","title":"A gain-of-function senescence bypass screen identifies the homeobox transcription factor DLX2 as a regulator of ATM-p53 signaling.","date":"2016","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/26833729","citation_count":21,"is_preprint":false},{"pmid":"24294369","id":"PMC_24294369","title":"Cancer testis antigen OY-TES-1 expression and serum immunogenicity in colorectal cancer: its relationship to clinicopathological parameters.","date":"2013","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/24294369","citation_count":21,"is_preprint":false},{"pmid":"32165291","id":"PMC_32165291","title":"DLX2 activates Wnt1 transcription and mediates Wnt/β-catenin signal to promote osteogenic differentiation of hBMSCs.","date":"2020","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/32165291","citation_count":20,"is_preprint":false},{"pmid":"18086710","id":"PMC_18086710","title":"Dlx2 homeobox gene transcriptional regulation of Trkb neurotrophin receptor expression during mouse retinal development.","date":"2007","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/18086710","citation_count":19,"is_preprint":false},{"pmid":"31891797","id":"PMC_31891797","title":"Actinidia Chinensis Planch Root extract attenuates proliferation and metastasis of hepatocellular carcinoma by inhibiting the DLX2/TARBP2/JNK/AKT pathway.","date":"2019","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31891797","citation_count":19,"is_preprint":false},{"pmid":"17969168","id":"PMC_17969168","title":"GAD isoforms exhibit distinct spatiotemporal expression patterns in the developing mouse lens: correlation with Dlx2 and Dlx5.","date":"2007","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/17969168","citation_count":19,"is_preprint":false},{"pmid":"33574458","id":"PMC_33574458","title":"Direct reprogramming of oligodendrocyte precursor cells into GABAergic inhibitory neurons by a single homeodomain transcription factor Dlx2.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33574458","citation_count":19,"is_preprint":false},{"pmid":"30861584","id":"PMC_30861584","title":"Expression of ventral telencephalon transcription factors ASCL1 and DLX2 in the early fetal human cerebral cortex.","date":"2019","source":"Journal of anatomy","url":"https://pubmed.ncbi.nlm.nih.gov/30861584","citation_count":18,"is_preprint":false},{"pmid":"21357706","id":"PMC_21357706","title":"Up-regulation of homeodomain genes, DLX1 and DLX2, by FLT3 signaling.","date":"2011","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/21357706","citation_count":18,"is_preprint":false},{"pmid":"15376329","id":"PMC_15376329","title":"Identification and characterization of a novel transcript down-regulated in Dlx1/Dlx2 and up-regulated in Pax6 mutant telencephalon.","date":"2004","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/15376329","citation_count":18,"is_preprint":false},{"pmid":"16301813","id":"PMC_16301813","title":"Identification of an HLA-A24-restricted OY-TES-1 epitope recognized by cytotoxic T-cells.","date":"2005","source":"Microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16301813","citation_count":17,"is_preprint":false},{"pmid":"22651134","id":"PMC_22651134","title":"Knockdown of OY-TES-1 by RNAi causes cell cycle arrest and migration decrease in bone marrow-derived mesenchymal stem cells.","date":"2012","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/22651134","citation_count":16,"is_preprint":false},{"pmid":"9188040","id":"PMC_9188040","title":"Dlx-2 homeobox gene controls neuronal differentiation in primary cultures of developing basal ganglia.","date":"1997","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/9188040","citation_count":16,"is_preprint":false},{"pmid":"7901126","id":"PMC_7901126","title":"The human brain homeogene, DLX-2: cDNA sequence and alignment with the murine homologue.","date":"1993","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/7901126","citation_count":16,"is_preprint":false},{"pmid":"26339343","id":"PMC_26339343","title":"Down-regulation of cancer/testis antigen OY-TES-1 attenuates malignant behaviors of hepatocellular carcinoma cells in vitro.","date":"2015","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26339343","citation_count":15,"is_preprint":false},{"pmid":"28529561","id":"PMC_28529561","title":"Serum immunoreactivity of cancer/testis antigen OY-TES-1 and its tissues expression in glioma.","date":"2017","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/28529561","citation_count":14,"is_preprint":false},{"pmid":"29787757","id":"PMC_29787757","title":"Dlx2 overexpression enhanced accumulation of type II collagen and aggrecan by inhibiting MMP13 expression in mice chondrocytes.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29787757","citation_count":13,"is_preprint":false},{"pmid":"35644412","id":"PMC_35644412","title":"LncRNA HOTTIP facilitates osteogenic differentiation in bone marrow mesenchymal stem cells and induces angiogenesis via interacting with TAF15 to stabilize DLX2.","date":"2022","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/35644412","citation_count":12,"is_preprint":false},{"pmid":"21397028","id":"PMC_21397028","title":"Proneural transcription factors Dlx2 and Pax6 are altered in adult SVZ neural precursor cells following striatal cell loss.","date":"2011","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/21397028","citation_count":12,"is_preprint":false},{"pmid":"33924205","id":"PMC_33924205","title":"Repeated Irradiation with γ-Ray Induces Cancer Stemness through TGF-β-DLX2 Signaling in the A549 Human Lung Cancer Cell Line.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33924205","citation_count":11,"is_preprint":false},{"pmid":"26136955","id":"PMC_26136955","title":"Effects of DLX2 overexpression on the osteogenic differentiation of MC3T3-E1 cells.","date":"2015","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26136955","citation_count":10,"is_preprint":false},{"pmid":"32862383","id":"PMC_32862383","title":"Cancer-testis Antigen OY-TES-1 Expression and Immunogenicity in Hepatocellular Carcinoma.","date":"2020","source":"Current medical science","url":"https://pubmed.ncbi.nlm.nih.gov/32862383","citation_count":9,"is_preprint":false},{"pmid":"36384139","id":"PMC_36384139","title":"TES-1/Tes and ZYX-1/Zyxin protect junctional actin networks under tension during epidermal morphogenesis in the C. elegans embryo.","date":"2022","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/36384139","citation_count":7,"is_preprint":false},{"pmid":"28447749","id":"PMC_28447749","title":"Dental and periodontal phenotypes of Dlx2 overexpression in mice.","date":"2017","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/28447749","citation_count":7,"is_preprint":false},{"pmid":"39034481","id":"PMC_39034481","title":"Efficient Dlx2-mediated astrocyte-to-neuron conversion and inhibition of neuroinflammation by NeuroD1.","date":"2024","source":"Developmental neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/39034481","citation_count":6,"is_preprint":false},{"pmid":"37365654","id":"PMC_37365654","title":"GABAergic neurons differentiated from BDNF- and Dlx2-modified neural stem cells restore disrupted neural circuits in brainstem stroke.","date":"2023","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37365654","citation_count":6,"is_preprint":false},{"pmid":"35514355","id":"PMC_35514355","title":"A Neural Crest-specific Overexpression Mouse Model Reveals the Transcriptional Regulatory Effects of Dlx2 During Maxillary Process Development.","date":"2022","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/35514355","citation_count":6,"is_preprint":false},{"pmid":"38946534","id":"PMC_38946534","title":"Osteocyte-derived exosomes regulate the DLX2/wnt pathway to alleviate osteoarthritis by mediating cartilage repair.","date":"2024","source":"Autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/38946534","citation_count":5,"is_preprint":false},{"pmid":"39104117","id":"PMC_39104117","title":"Characteristic changes in astrocyte properties during astrocyte-to-neuron conversion induced by NeuroD1/Ascl1/Dlx2.","date":"2024","source":"Neural regeneration research","url":"https://pubmed.ncbi.nlm.nih.gov/39104117","citation_count":4,"is_preprint":false},{"pmid":"35463688","id":"PMC_35463688","title":"Immunohistochemistry Study of OY-TES-1 Location in Fetal and Adult Human Tissues.","date":"2022","source":"Journal of healthcare engineering","url":"https://pubmed.ncbi.nlm.nih.gov/35463688","citation_count":2,"is_preprint":false},{"pmid":"37286519","id":"PMC_37286519","title":"JMJD3 is Involved in Intracranial Aneurysm Development by Regulating DLX2 Expression through H3K27me3 Modification.","date":"2023","source":"The Tohoku journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37286519","citation_count":2,"is_preprint":false},{"pmid":"27315306","id":"PMC_27315306","title":"Overexpression of Dlx2 leads to postnatal condyle degradation.","date":"2016","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/27315306","citation_count":2,"is_preprint":false},{"pmid":"10470137","id":"PMC_10470137","title":"Establishment and characterization of human immature teratoma cell line (TES-1).","date":"1999","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/10470137","citation_count":2,"is_preprint":false},{"pmid":"36891149","id":"PMC_36891149","title":"Effects of Dlx2 overexpression on the genes associated with the maxillary process in the early mouse embryo.","date":"2023","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36891149","citation_count":1,"is_preprint":false},{"pmid":"41533791","id":"PMC_41533791","title":"DLX2 acts as a pioneer factor and drives Msx1+ ectomesenchyme formation from embryonic stem cells.","date":"2026","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/41533791","citation_count":0,"is_preprint":false},{"pmid":"41244921","id":"PMC_41244921","title":"DLX2 promotes gastric cancer epithelial- mesenchymal transition and malignant progression through the PI3K/AKT signaling pathway.","date":"2025","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41244921","citation_count":0,"is_preprint":false},{"pmid":"21779750","id":"PMC_21779750","title":"Dlx2 over-expression: a possible mechanism for first branchial arch malformation.","date":"2011","source":"Shanghai kou qiang yi xue = Shanghai journal of stomatology","url":"https://pubmed.ncbi.nlm.nih.gov/21779750","citation_count":0,"is_preprint":false},{"pmid":"41428155","id":"PMC_41428155","title":"OY-TES-1 Splice Variant V5a in Glioma: A Driver of Malignancy and Potential Therapeutic Target.","date":"2025","source":"Current medical science","url":"https://pubmed.ncbi.nlm.nih.gov/41428155","citation_count":0,"is_preprint":false},{"pmid":"41761000","id":"PMC_41761000","title":"DLX2 marks an immunosuppressive dendritic-cell program that reshapes cytotoxic immunity and marks a tolerogenic microenvironment in lung adenocarcinoma.","date":"2026","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41761000","citation_count":0,"is_preprint":false},{"pmid":"14703475","id":"PMC_14703475","title":"[Expression of homeobox gene Msx-1, Msx-2 and Dlx-2 during murine mandibular first molar development].","date":"2003","source":"Zhonghua kou qiang yi xue za zhi = Zhonghua kouqiang yixue zazhi = Chinese journal of stomatology","url":"https://pubmed.ncbi.nlm.nih.gov/14703475","citation_count":0,"is_preprint":false},{"pmid":"42180979","id":"PMC_42180979","title":"PTTG1-DLX2 axis drives malignant progression of lung adenocarcinoma by activating the WNT/β-catenin signaling pathway.","date":"2026","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/42180979","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.28.679022","title":"The DLX/Notch axis is necessary for spatiotemporal regulation of neural cell fate","date":"2025-09-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.28.679022","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.30.662293","title":"One-step induction of human GABAergic neurons promotes presynaptic development & synapse maturation","date":"2025-07-04","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.30.662293","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.18.643955","title":"Wnt signaling restores evolutionary loss of regenerative potential in  <i>Hydra</i>","date":"2025-03-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.18.643955","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.03.626438","title":"Expanding GABAergic Neuronal Diversity in PSC-Derived Disease Models","date":"2024-12-04","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.03.626438","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49730,"output_tokens":9009,"usd":0.142162,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19053,"output_tokens":5305,"usd":0.113945,"stage2_stop_reason":"end_turn"},"total_usd":0.256107,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"The noncoding RNA Evf-2, transcribed from the Dlx-5/6 ultraconserved region, forms a stable complex with DLX-2 protein in vivo and specifically cooperates with DLX-2 to increase transcriptional activity of the Dlx-5/6 enhancer in a target- and homeodomain-specific manner, identifying a mechanism whereby an ncRNA activates transcription by directly influencing homeodomain protein activity.\",\n      \"method\": \"In vivo co-immunoprecipitation (stable Evf-2/DLX-2 complex), reporter/transcription assays, RNA-protein interaction studies\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal in vivo complex formation plus functional reporter assays in a single focused study\",\n      \"pmids\": [\"16705037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Null mutation of Dlx-2 in mice causes abnormal differentiation within the forebrain and respecification of a subset of cranial neural crest cells, leading to abnormal morphogenesis of skeletal elements derived from the proximal first and second branchial arches, demonstrating that Dlx-2 is required for branchial arch development and forebrain differentiation.\",\n      \"method\": \"Gene targeting (null mutation), histological and skeletal phenotype analysis in homozygous mutant mice\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with defined cellular phenotype, replicated across multiple subsequent studies\",\n      \"pmids\": [\"7590232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Mice lacking both Dlx-1 and Dlx-2 show a time-dependent block in striatal differentiation: early born neurons migrate into a striatum-like region, but later born neurons accumulate in the proliferative zone, demonstrating that Dlx-1 and Dlx-2 are required for development of the striatal subventricular zone and differentiation of late-born striatal matrix neurons.\",\n      \"method\": \"Double knockout mouse, histological and marker analysis of striatal phenotype\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean double knockout with defined compartment-specific cellular phenotype, replicated in follow-up studies\",\n      \"pmids\": [\"9247261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Dlx-1 and Dlx-2 double null mice fail to develop maxillary molar teeth; heterologous recombination experiments showed that Dlx-1/2 mutant ectomesenchyme loses odontogenic potential and its cells adopt a chondrogenic fate instead (marked by Barx1/Sox9 expression), demonstrating that Dlx-1 and Dlx-2 specify odontogenic identity in cranial neural crest-derived ectomesenchyme.\",\n      \"method\": \"Double knockout mouse, heterologous tissue recombination, molecular marker analysis (Barx1, Sox9)\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout plus tissue recombination with fate-marker evidence, multiple orthogonal approaches\",\n      \"pmids\": [\"9428417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Antisense oligonucleotide blockade of Dlx-2 expression in primary basal ganglia cultures caused specific decreases in MAP2 expression and dendrite outgrowth, and increased cell proliferation, demonstrating that Dlx-2 regulates neuronal differentiation by promoting exit from the mitotic cycle and growth of MAP2-positive dendrites.\",\n      \"method\": \"Antisense oligonucleotide knockdown in primary cultures, MAP2 immunostaining, cell proliferation assays\",\n      \"journal\": \"Journal of molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — antisense knockdown in primary culture with two phenotypic readouts (dendrite morphology, proliferation), single lab\",\n      \"pmids\": [\"9188040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Dlx-1 and Dlx-2 mutations disrupt proximodistal patterning of the branchial arches in a region-specific manner; single Dlx-1 mutants reveal distinct proximal skeletal and soft tissue defects, and Dlx-1/2 double mutants show unique additional abnormalities including absence of maxillary molars, establishing distinct and overlapping roles for Dlx-1 and Dlx-2 in craniofacial patterning.\",\n      \"method\": \"Single and double knockout mouse models, skeletal and soft tissue analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple clean knockout genotypes with defined skeletal phenotypes, replicated across labs\",\n      \"pmids\": [\"9187081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Dlx2 epithelial expression in the first branchial arch is regulated by BMP4 (planar signaling), while mesenchymal expression is regulated by FGF8 from the overlying epithelium; FGF8 also inhibits Dlx2 epithelial expression via a mesenchyme-dependent signaling pathway. Transgenic reporter mapping of a 3.8 kb upstream Dlx2 sequence confirmed epithelial-specific regulatory elements.\",\n      \"method\": \"Transgenic reporter (lacZ) analysis, signaling factor treatment of explants, regulatory element mapping\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic reporter plus signaling perturbations, single lab, two orthogonal approaches\",\n      \"pmids\": [\"10603340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"BMP-2 stimulates Dlx-2 expression in chondroblasts, and antisense oligonucleotide blockade of Dlx-2 abolishes BMP-2-mediated transcriptional activation of the chondrocyte-specific Col2alpha1 enhancer; dominant-negative Smad1 similarly blocks BMP-2 signaling to Col2alpha1, establishing Dlx-2 as a downstream mediator of BMP-2/Smad signaling required for Col2alpha1 gene expression.\",\n      \"method\": \"Antisense oligonucleotide knockdown, dominant-negative Smad1, Col2alpha1 enhancer reporter assays\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antisense knockdown plus dominant-negative epistasis plus reporter assay, single lab\",\n      \"pmids\": [\"11445007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PITX2 activates the Dlx2 promoter (~45-fold in CHO cells) by binding bicoid and bicoid-like elements in the Dlx2 promoter; Msx2 represses the Dlx2 promoter by competing with PITX2 for binding to the bicoid element; co-expression of PITX2 and Msx2 results in transcriptional antagonism at the Dlx2 promoter.\",\n      \"method\": \"Luciferase reporter assays, EMSA (electrophoretic mobility shift assay), RT-PCR, Western blot\",\n      \"journal\": \"Gene expression\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA plus reporter assays demonstrating direct binding and functional antagonism, single lab\",\n      \"pmids\": [\"11763998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In the Dlx1/2 double null retina, late-born retinal ganglion cells (RGCs) are lost due to increased apoptosis and there is ectopic expression of Crx in the ganglion cell layer, while amacrine and horizontal cell differentiation is relatively unaffected, demonstrating that Dlx1 and Dlx2 are required for terminal differentiation and survival of late-born RGCs.\",\n      \"method\": \"Double knockout mouse, histological and marker analysis of retinal phenotype, TUNEL apoptosis assay\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean double knockout with cell-type-specific phenotype, ectopic marker expression as fate readout\",\n      \"pmids\": [\"15604100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Ectopic expression of Dlx2 in the chick neural tube via electroporation dramatically inhibits neural crest cell migration, induces cell aggregation, and in branchial arch mesenchyme induces N-cadherin and NCAM expression and increases mesenchymal condensation, demonstrating that Dlx2 regulates ectomesenchymal cell adhesion.\",\n      \"method\": \"In ovo electroporation, immunostaining for N-cadherin and NCAM, cell migration assay\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function in ovo with defined adhesion molecule readouts, single lab\",\n      \"pmids\": [\"15848386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Chromatin immunoprecipitation (ChIP) identified Msx2 as a direct downstream target of Dlx2; Dlx2 activates the Msx2 promoter and binds DNA as both monomer and dimer; LEF-1 physically interacts with Dlx2 (by co-immunoprecipitation and protein pull-down) and synergistically activates the Msx2 promoter with Dlx2; Msx2 can auto-regulate its own promoter and represses Dlx2-mediated activation in a dose-specific manner.\",\n      \"method\": \"ChIP, co-immunoprecipitation, protein pull-down, luciferase reporter assays, deletion analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP plus reciprocal Co-IP/pulldown plus functional reporter, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"17068080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Dlx1 and Dlx2 transcription factors repress oligodendrocyte precursor cell (OPC) formation in the ventral telencephalon; progenitors from Dlx1/2 mutant ventral telencephalon transplanted into wild-type mice do not produce neurons but differentiate into myelinating oligodendrocytes that survive into adulthood, demonstrating that Dlx1&2 act on a common progenitor to determine neuronal versus oligodendroglial cell fate.\",\n      \"method\": \"Double knockout mouse, progenitor transplantation into wild-type host, myelination/marker analysis\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout plus transplantation rescue experiment with cell-fate readout, independent replicated finding\",\n      \"pmids\": [\"17678855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"DLX2 binds directly to a specific region of the TrkB promoter in retinal neuroepithelium (demonstrated by ChIP), activates TrkB transcription in vitro, and ectopic Dlx2 expression in retinal explants activates TrkB expression while Dlx2 knockdown in primary retinal cultures reduces TrkB expression, establishing TrkB as a direct transcriptional target of DLX2 in RGC differentiation.\",\n      \"method\": \"ChIP, luciferase reporter assay, ectopic expression in retinal explants, siRNA knockdown in primary cultures\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP plus reporter plus gain- and loss-of-function in primary tissue, multiple orthogonal methods\",\n      \"pmids\": [\"18086710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Dlx2 is necessary for neurogenesis of virtually all olfactory bulb interneurons arising from the lateral subependymal zone (SEZ) as shown by retroviral loss-of-function, and promotes specification of periglomerular neurons (PGNs) toward a dopaminergic fate; this PGN subtype specification requires interaction between Dlx2 and Pax6, as Pax6 deletion blocks Dlx2-mediated PGN specification.\",\n      \"method\": \"Retroviral cell-autonomous loss-of-function, genetic epistasis (Pax6 conditional knockout), immunostaining of neuronal subtypes\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-autonomous retroviral knockdown plus genetic epistasis, two orthogonal approaches in same study\",\n      \"pmids\": [\"18562615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Dlx2 directly activates the Arx GABAergic enhancer: Dlx overexpression induces ectopic endogenous Arx expression, loss of Dlx expression reduces Arx expression, and Arx is necessary for Dlx-dependent promotion of interneuron migration but not for GABAergic cell fate commitment, establishing a direct genetic hierarchy between Dlx2 and Arx in telencephalic GABAergic neuron development.\",\n      \"method\": \"Gain-of-function (Dlx overexpression), loss-of-function (Dlx/Arx mutants), enhancer reporter assay, genetic epistasis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain- and loss-of-function combined with epistasis across multiple mutant backgrounds\",\n      \"pmids\": [\"18923043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The Rb/E2F pathway directly regulates the Dlx1/Dlx2 bigene cluster: Rb deficiency dramatically reduces Dlx1 and Dlx2 expression; repressor E2Fs bind and inhibit transcription at the Dlx1/Dlx2 promoters and the I12b forebrain enhancer in vitro and in vivo (ChIP), establishing that the cell cycle machinery modulates neuronal differentiation and migration by direct repression of Dlx gene expression.\",\n      \"method\": \"Rb knockout mouse, ChIP, in vitro reporter assays, interneuron subtype and migration analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP plus knockout plus reporter, multiple orthogonal methods demonstrating direct regulatory relationship\",\n      \"pmids\": [\"22699903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Both the I12b and URE2 cis-regulatory elements at the Dlx1/2 locus are direct transcriptional targets of DLX2 and require Dlx1 and Dlx2 expression for proper enhancer activity, as demonstrated by in vivo Cre-based fate mapping and Dlx1/2 mutant analysis.\",\n      \"method\": \"Cre-transgenic mice, fate mapping (Z/EG reporter), Dlx1/2 mutant analysis, enhancer activity assays\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo enhancer activity assay in Dlx mutant background, single lab\",\n      \"pmids\": [\"19026749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DLX2 promotes lineage transition from neural stem cells (NSCs) to transit-amplifying precursors (TAPs) and enhances the proliferative response of neuronal progenitors to EGF, demonstrating that DLX2 and EGFR signaling interact at multiple steps to coordinate proliferation in the postnatal subventricular zone.\",\n      \"method\": \"Forced DLX2 expression in SVZ-isolated NSCs, in vitro proliferation and lineage assays, EGF response measurement\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined in vitro gain-of-function with lineage and proliferation readouts, single lab\",\n      \"pmids\": [\"19683576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Dlx-2 is induced in cancer cells by glucose deprivation in a reactive oxygen species (ROS)-dependent manner; Dlx-2 shRNA prevents metabolic stress-induced increases in mitochondrial ROS and suppresses metabolic stress-induced necrosis (measured by PI-positive cells, HMGB1 and LDH release), demonstrating Dlx-2's role in regulating metabolic stress-induced necrosis.\",\n      \"method\": \"shRNA knockdown, propidium iodide staining, HMGB1/LDH release assay, mitochondrial ROS measurement\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA knockdown with multiple mechanistic readouts in cancer cell lines, single lab\",\n      \"pmids\": [\"21917150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Dlx2 acts as a direct transcriptional repressor of TGFβ receptor II (TGFβRII) gene expression, thereby reducing canonical Smad-dependent TGFβ signaling, p21CIP1 expression, and increasing c-Myc expression; additionally, Dlx2 directly induces betacellulin expression to promote cell survival via EGF receptor signaling, thus counteracting TGFβ-induced cell-cycle arrest and apoptosis.\",\n      \"method\": \"Reporter assays, Western blot, gene expression analysis, overexpression/knockdown in mammary epithelial cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct repressor function demonstrated by reporter assays plus pathway marker analysis, single lab\",\n      \"pmids\": [\"21897365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Dlx-2 induces epithelial-mesenchymal transition (EMT) and glycolytic switch by activating Snail expression; Dlx-2 is induced by TGF-β and Wnt, and mediates their induction of EMT, glycolytic switch, and suppression of cytochrome c oxidase (COX) subunit expression (including COXVIc) in a Snail-dependent manner.\",\n      \"method\": \"shRNA knockdown, gene expression analysis, Western blot, pathway perturbation with TGF-β/Wnt in cancer cell lines\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA knockdown plus signaling perturbations with defined downstream target readouts, single lab\",\n      \"pmids\": [\"25651912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Dlx-2 induces expression of glutaminase (GLS1), a key glutamine metabolism enzyme; GLS1 shRNA, glutamine deprivation, and metabolism inhibitors prevent Dlx-2-, TGF-β-, Wnt-, and Snail-induced EMT and glycolytic switch; Dlx-2/GLS1 inhibition also decreases Snail mRNA through p53-dependent upregulation of Snail-targeting microRNAs.\",\n      \"method\": \"shRNA knockdown, pharmacological inhibitors, gene expression analysis, in vivo metastasis assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA plus pharmacological inhibition with multiple downstream readouts and in vivo validation, single lab\",\n      \"pmids\": [\"26771232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DLX2 expression reduces protein components of the TTI1/TTI2/TEL2 complex (required for proper folding and stabilization of ATM and other PIKK kinases), leading to reduced ATM-p53 signaling and bypass of replicative senescence, as identified in a gain-of-function senescence bypass screen.\",\n      \"method\": \"Gain-of-function screen, protein complex component analysis, ATM-p53 signaling assays, replicative lifespan measurement\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional screen with mechanistic follow-up on TTI/TEL2 complex, single lab\",\n      \"pmids\": [\"26833729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DLX2 expression is induced by ionizing radiation in a Smad2/3-dependent manner; DLX2 overexpression alone induces EMT, migration, invasion, and cancer stem cell marker expression; DLX2 depletion abolishes radiation-induced EMT and increases radiation sensitivity, demonstrating that DLX2 mediates radiation-induced EMT and radioresistance downstream of Smad2/3 signaling.\",\n      \"method\": \"siRNA knockdown, DLX2 overexpression, Smad2/3 knockdown, colony formation assay, migration/invasion assays in cancer cell lines\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic siRNA knockdown of Smad2/3 upstream plus DLX2 gain/loss of function, single lab\",\n      \"pmids\": [\"26799321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BMP type I receptor ALK-2 mediates DLX2 induction in glioma-initiating cells; DLX2 promotes apoptosis and neural differentiation of glioma-initiating cells; valproic acid induces BMP2/BMP4/ACVR1/DLX2 expression with increased Smad1/5 phosphorylation, and silencing ALK-2 or DLX2 partially suppresses VPA-induced apoptosis, establishing DLX2 as a pro-apoptotic BMP target gene in glioblastoma.\",\n      \"method\": \"siRNA knockdown, VPA treatment, Smad phosphorylation analysis, orthotopic mouse transplantation model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA epistasis plus in vivo orthotopic model, single lab\",\n      \"pmids\": [\"28459464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DLX1 and DLX2 function as direct transcriptional activators of Brn3b expression in retinal ganglion cells; Dlx2 knockdown in primary embryonic retinal cultures reduces Brn3b expression, and Dlx2 gain-of-function in utero is sufficient for Brn3b expression; triple Dlx1/Dlx2/Brn3b knockout retinas show near-total RGC loss with marked increase in amacrine cells, a more severe phenotype than either double or single knockouts.\",\n      \"method\": \"Triple knockout mouse, Dlx2 knockdown in primary cultures, in utero gain-of-function, marker and cell-fate analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (triple KO), gain- and loss-of-function with cell-fate readouts, multiple orthogonal approaches\",\n      \"pmids\": [\"28356311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DLX2 directly drives Gad1, Gad2, and Vgat expression in cortical interneurons (demonstrated by conditional knockout evidence); Dlx1&2 conditional knockouts show reduced mIPSC amplitude, fewer GABAergic synapses on excitatory neurons, reduced mIPSC frequency, hypoplastic dendrites, fewer excitatory synapses, and reduced GRIN2B expression.\",\n      \"method\": \"Conditional knockout (Dlx1, Dlx2, Dlx1&2 CKOs), electrophysiology (mIPSC), immunostaining, gene expression analysis\",\n      \"journal\": \"Cerebral cortex\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple conditional knockouts with electrophysiological and molecular readouts, multiple orthogonal methods\",\n      \"pmids\": [\"29028947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DLX2 directly binds to Dlx2-response cis-acting elements in the promoters of Osteocalcin (OCN) and Alp genes (demonstrated by ChIP and site-directed mutagenesis of the binding elements) and transactivates their expression, thereby promoting osteogenic differentiation of BMSCs and MC3T3-E1 cells without affecting Runx2, Dlx5, Msx2, or Osterix levels.\",\n      \"method\": \"ChIP assay, site-directed mutagenesis, luciferase reporter assay, ALP activity, Alizarin red staining, in vivo implantation in nude mice\",\n      \"journal\": \"International journal of oral science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP plus mutagenesis of binding sites plus functional reporter plus in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"30880332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DLX2 acts as a transcription factor for WNT1, directly binding the WNT1 promoter (confirmed by ChIP), activating Wnt/β-catenin signaling to promote osteogenic differentiation of hBMSCs; inhibition of β-catenin by FH535 restrains DLX2-enhanced osteogenic differentiation.\",\n      \"method\": \"ChIP assay, reporter assay (implied), Western blot, ALP activity, Alizarin red staining, β-catenin inhibitor rescue\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus pharmacological epistasis with functional osteogenic readouts, single lab\",\n      \"pmids\": [\"32165291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Misexpression of Dlx2 alone in postnatal mouse oligodendrocyte precursor cells (OPCs) is sufficient to switch their fate to GABAergic neurons within 2 days by downregulating Olig2 and upregulating a network of inhibitory neuron transcripts; after two weeks some OPC-derived neurons generate action potentials and form clusters of GABAergic synaptic proteins.\",\n      \"method\": \"Dlx2 misexpression in OPCs, transcriptome analysis, electrophysiology, immunostaining of synaptic markers\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function with defined molecular (Olig2/Dlx2 switch) and functional (electrophysiology) readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33574458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Dlx2 overexpression in chondroblasts increases accumulation of aggrecan and type II collagen by directly repressing MMP13 expression; luciferase reporter and ChIP analysis demonstrated that Dlx2 inhibits MMP13 expression by directly binding to two Dlx2-response elements in the MMP13 promoter.\",\n      \"method\": \"Dlx2 overexpression, luciferase reporter assay, ChIP, Western blot, qRT-PCR\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP plus mutagenesis-based reporter plus protein-level readouts, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"29787757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"JMJD3 demethylase promotes DLX2 expression by inhibiting H3K27me3 modification at the DLX2 locus; JMJD3 depletion phenocopies DLX2 loss (suppressed vascular smooth muscle cell proliferation, promoted apoptosis), and DLX2 overexpression rescues the effects of JMJD3 knockdown, demonstrating an epigenetic regulatory axis controlling DLX2 in intracranial aneurysm.\",\n      \"method\": \"siRNA knockdown of JMJD3 and DLX2, H3K27me3 chromatin analysis, rescue overexpression, in vivo model\",\n      \"journal\": \"The Tohoku journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic knockdown/rescue with epigenetic mark analysis, single lab\",\n      \"pmids\": [\"37286519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DLX2 acts as a pioneer factor by forming a complex with LAP2α (lamina-associated polypeptide 2, isoform alpha) through a 38-amino-acid homeodomain motif, interacting with nucleosomes to promote chromatin remodeling and activate a procraniofacial ectomesenchymal gene network; disrupting DLX2-LAP2α interaction or silencing Dlx2 targets markedly diminished ectomesenchymal differentiation of murine ESCs.\",\n      \"method\": \"ESC differentiation assay, co-immunoprecipitation (DLX2-LAP2α complex), domain mutagenesis, chromatin remodeling assays, scRNA-seq trajectory analysis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — complex formation by Co-IP plus domain mutagenesis plus functional differentiation assay, multiple orthogonal methods in single study\",\n      \"pmids\": [\"41533791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DLX2 directly represses Notch signaling genes and glial fate-promoting transcription factors in ventral telencephalon progenitors, as revealed by single-cell multi-omic analysis; DLX2 maintains progenitor populations in a secondary proliferative zone of the ventral subventricular zone and facilitates neural differentiation by spatiotemporal-context-dependent Notch pathway repression.\",\n      \"method\": \"Single-cell whole genome spatial transcriptomics, multi-omic approach, DLX2 regulatory network analysis in ventral telencephalon\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multi-omic single-cell profiling with direct regulatory network evidence but preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TAF15 physically interacts with lncRNA HOTTIP and stabilizes DLX2 protein (demonstrated by RNA immunoprecipitation and RNA pulldown), and this HOTTIP-TAF15-DLX2 axis promotes osteogenic differentiation and angiogenesis in hBMSCs.\",\n      \"method\": \"RNA immunoprecipitation (RIP), RNA pulldown, Western blot, ALP activity, Alizarin red staining\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RIP and RNA pulldown demonstrating TAF15-HOTTIP interaction with DLX2 stabilization as functional readout, single lab\",\n      \"pmids\": [\"35644412\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DLX2 is a homeodomain transcription factor that acts as a pioneer factor forming complexes with partners including LAP2α (to remodel chromatin) and Evf-2 ncRNA (to enhance Dlx-5/6 transcription), directly activates targets such as Arx, Brn3b, TrkB, Gad1/2/Vgat, Osteocalcin, Alp, Wnt1, and MMP13 (or represses TGFβRII and Notch signaling genes), and is regulated upstream by BMP-2/Smad, FGF8, BMP4, Rb/E2F, and JMJD3-H3K27me3; it is required for striatal neuron differentiation, GABAergic interneuron specification and migration, neuronal versus oligodendroglial fate determination, retinal ganglion cell survival, olfactory bulb periglomerular neuron subtype specification (in cooperation with Pax6), craniofacial branchial arch patterning, odontogenic specification, and osteogenic/chondrogenic differentiation, while in cancer contexts it counteracts TGFβ-induced growth arrest, drives EMT via Snail/glutaminase, and bypasses senescence by destabilizing the ATM-activating TTI/TEL2 complex.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"DLX2 is a homeodomain transcription factor that governs cell-fate specification and differentiation in neural, craniofacial, and skeletal lineages, and is redeployed in cancer to drive metabolic and epithelial-mesenchymal reprogramming [#1, #2, #21]. In the forebrain, DLX2 (largely redundantly with DLX1) is required for striatal subventricular zone development and differentiation of late-born matrix neurons [#2], for GABAergic interneuron specification and migration, and for the neuronal-versus-oligodendroglial fate decision in ventral telencephalic progenitors, where loss of Dlx1/2 reroutes progenitors to a myelinating oligodendrocyte fate [#12]. It enforces these programs through a defined transcriptional hierarchy: DLX2 directly activates the Arx GABAergic enhancer to drive interneuron migration [#15] and directly induces Gad1, Gad2, and Vgat to confer GABAergic synaptic identity [#27], and its forced expression alone is sufficient to convert oligodendrocyte precursors into functional GABAergic neurons by repressing Olig2 [#30]. In the retina, DLX1/2 directly activate Brn3b and TrkB to support terminal differentiation and survival of late-born retinal ganglion cells [#13, #26]. DLX2 also specifies odontogenic identity in cranial neural crest-derived ectomesenchyme and patterns the branchial arches, acting in part as a pioneer factor that binds nucleosomes via a homeodomain motif and partners with LAP2alpha to remodel chromatin and activate a procraniofacial gene network [#1, #3, #33]. In osteogenic and chondrogenic contexts it directly transactivates Osteocalcin, Alp, and Wnt1 while repressing MMP13 [#28, #29, #31]. Its expression is set by upstream signaling and chromatin inputs including BMP/Smad, FGF8, PITX2/Msx2 antagonism, Rb/E2F repression, and JMJD3-mediated H3K27me3 demethylation [#6, #8, #16, #32]. In cancer, DLX2 counteracts TGFbeta-induced growth arrest by directly repressing TGFbeta receptor II [#20], drives EMT and a glycolytic switch through Snail and glutaminase (GLS1) [#21, #22], and bypasses replicative senescence by destabilizing the TTI1/TTI2/TEL2 complex to attenuate ATM-p53 signaling [#23].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established that Dlx2 is genetically required in vivo, defining its essential roles in forebrain differentiation and branchial arch morphogenesis before any molecular target was known.\",\n      \"evidence\": \"Null-mutant mouse with histological and skeletal phenotyping\",\n      \"pmids\": [\"7590232\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets not identified\", \"Did not distinguish cell-autonomous from non-autonomous effects\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined the developmental scope of Dlx1/Dlx2 by showing distinct and overlapping requirements in striatal neuron differentiation, odontogenic ectomesenchyme identity, and proximodistal arch patterning, establishing functional redundancy within the bigene cluster.\",\n      \"evidence\": \"Single and double knockout mice, tissue recombination, fate-marker analysis, antisense knockdown in primary cultures\",\n      \"pmids\": [\"9247261\", \"9428417\", \"9187081\", \"9188040\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of redundancy with Dlx1 not resolved at the molecular level\", \"No direct target genes defined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Placed Dlx2 downstream of epithelial-mesenchymal signaling by showing BMP4 and FGF8 differentially control its tissue-specific expression in the first branchial arch.\",\n      \"evidence\": \"Transgenic lacZ reporter mapping plus signaling-factor treatment of explants\",\n      \"pmids\": [\"10603340\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect transcriptional inputs not separated\", \"Regulatory elements mapped only coarsely\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified upstream transcriptional regulators of Dlx2, with BMP-2/Smad1 driving its expression in chondroblasts and PITX2/Msx2 acting as competing activator/repressor at the Dlx2 promoter.\",\n      \"evidence\": \"Antisense knockdown, dominant-negative Smad1, EMSA and luciferase reporter assays\",\n      \"pmids\": [\"11445007\", \"11763998\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous occupancy of the bicoid elements not shown by ChIP\", \"In vivo relevance of PITX2/Msx2 antagonism untested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Extended Dlx1/2 requirement to the retina, showing they are needed for terminal differentiation and survival of late-born retinal ganglion cells.\",\n      \"evidence\": \"Double knockout mouse with marker analysis and TUNEL apoptosis assay\",\n      \"pmids\": [\"15604100\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct targets in RGCs not yet identified\", \"Cause of ectopic Crx expression unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Linked Dlx2 to cell adhesion, showing gain-of-function induces N-cadherin/NCAM and mesenchymal condensation while blocking neural crest migration.\",\n      \"evidence\": \"In ovo electroporation with adhesion-molecule immunostaining and migration assays\",\n      \"pmids\": [\"15848386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Adhesion genes not shown to be direct targets\", \"Mechanism of migration arrest unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Revealed a non-protein partner mechanism: the ncRNA Evf-2 forms a stable complex with DLX-2 and cooperatively boosts Dlx-5/6 enhancer activity, showing ncRNAs can directly modulate homeodomain factor activity.\",\n      \"evidence\": \"In vivo co-immunoprecipitation and reporter/transcription assays\",\n      \"pmids\": [\"16705037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Evf-2/DLX-2 binding unknown\", \"Generality to other Dlx targets untested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Provided the first direct DNA targets and a protein cofactor: DLX2 binds and activates the TrkB and Msx2 promoters, dimerizes on DNA, and synergizes with LEF-1, while also repressing oligodendrocyte fate to control the neuron-vs-glia decision.\",\n      \"evidence\": \"ChIP, reciprocal Co-IP/pulldown, reporter assays, knockout plus progenitor transplantation\",\n      \"pmids\": [\"18086710\", \"17068080\", \"17678855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide target set not defined\", \"How DLX2 switches between activation and repression unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Built the GABAergic transcriptional hierarchy and its upstream control, showing DLX2 directly activates the Arx enhancer and its own I12b/URE2 elements, cooperates with Pax6 for periglomerular dopaminergic fate, and is directly repressed by Rb/E2F.\",\n      \"evidence\": \"Gain/loss-of-function, enhancer reporter assays, retroviral loss-of-function, genetic epistasis, ChIP, Rb knockout\",\n      \"pmids\": [\"18923043\", \"18562615\", \"19026749\", \"22699903\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Arx separates migration from fate commitment but the fate-commitment effector is unidentified\", \"Coupling of cell cycle exit to differentiation not fully mechanistic\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected DLX2 to progenitor proliferation, showing it drives the NSC-to-transit-amplifying-precursor transition and synergizes with EGFR signaling in the postnatal SVZ.\",\n      \"evidence\": \"Forced expression in SVZ NSCs with in vitro lineage and proliferation assays\",\n      \"pmids\": [\"19683576\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional targets in proliferation control unknown\", \"In vivo requirement not established here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Reframed DLX2 as an oncogenic effector, showing it directly represses TGFbetaRII to evade growth arrest and is induced by metabolic stress to regulate ROS-dependent necrosis in cancer cells.\",\n      \"evidence\": \"Reporter assays, overexpression/knockdown in mammary epithelial cells, shRNA with necrosis and mitochondrial ROS readouts\",\n      \"pmids\": [\"21897365\", \"21917150\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding to TGFbetaRII promoter shown only by reporter assays\", \"Mechanism of ROS-dependent induction undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the EMT/metabolic program downstream of DLX2, showing it is induced by TGFbeta and Wnt and drives EMT and glycolytic switch via Snail and the metabolic enzyme glutaminase.\",\n      \"evidence\": \"shRNA knockdown, pathway perturbations, in vivo metastasis assay\",\n      \"pmids\": [\"25651912\", \"26771232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Snail and GLS1 not shown to be direct DLX2 transcriptional targets\", \"Cancer-type generality untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established context-dependent dual roles in transformation: DLX2 mediates Smad2/3-driven radiation-induced EMT and radioresistance and bypasses senescence by destabilizing the TTI/TEL2 complex and ATM-p53 signaling, yet acts pro-apoptotically downstream of BMP/ALK-2 in glioma cells.\",\n      \"evidence\": \"Gain-of-function senescence screen, siRNA epistasis, ATM-p53 assays, orthotopic mouse model\",\n      \"pmids\": [\"26799321\", \"26833729\", \"28459464\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Basis for opposite pro-apoptotic vs pro-survival outputs unresolved\", \"Mechanism of TTI/TEL2 destabilization not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Consolidated DLX2 as a direct osteo/chondrogenic regulator, showing it binds and transactivates Osteocalcin, Alp, and Wnt1 while directly repressing MMP13, with Wnt/beta-catenin as a key downstream axis.\",\n      \"evidence\": \"ChIP, site-directed mutagenesis, reporter assays, ALP/Alizarin red staining, in vivo implantation, beta-catenin inhibitor rescue\",\n      \"pmids\": [\"30880332\", \"32165291\", \"29787757\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay with canonical osteogenic factors (Runx2/Osterix) left unaffected and unexplained\", \"Coordination of activator vs repressor target selection unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified an epigenetic upstream control, with JMJD3 demethylase removing H3K27me3 at the DLX2 locus to permit its expression in vascular smooth muscle cells.\",\n      \"evidence\": \"siRNA knockdown/rescue, H3K27me3 chromatin analysis, in vivo aneurysm model\",\n      \"pmids\": [\"37286519\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct recruitment of JMJD3 to the locus not shown\", \"Relevance beyond the aneurysm context unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined DLX2's molecular mode of action as a pioneer factor, showing it engages nucleosomes through a homeodomain motif and partners with LAP2alpha to remodel chromatin and activate a procraniofacial ectomesenchymal gene network.\",\n      \"evidence\": \"ESC differentiation, Co-IP, domain mutagenesis, chromatin remodeling assays, scRNA-seq trajectory analysis\",\n      \"pmids\": [\"41533791\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide pioneering target catalogue not defined\", \"Whether LAP2alpha partnership operates in non-craniofacial DLX2 functions unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how DLX2 selects between transcriptional activation and repression and between pro-differentiation and oncogenic outputs across tissues, and how its pioneer-factor activity and cofactor choice (LAP2alpha, LEF-1, Evf-2, Pax6) are coordinated genome-wide.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking activator vs repressor target choice\", \"No genome-wide pioneer-binding map across cell types\", \"Context-dependent pro-apoptotic vs pro-survival switch unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [11, 13, 15, 20, 28, 31]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [11, 13, 28, 29, 31]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [11, 13, 28, 33]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [11, 13, 15, 28, 31]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2, 3, 12, 26]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [33, 32]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [20, 29, 25]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [21, 22, 23, 24]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LAP2alpha\", \"LEF-1\", \"Evf-2\", \"Pax6\", \"TAF15\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}