Affinage

DLX2

Homeobox protein DLX-2 · UniProt Q07687

Length
328 aa
Mass
34.2 kDa
Annotated
2026-06-09
95 papers in source corpus 35 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1995 High

    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

    PMID:7590232

    Open questions at the time
    • Direct transcriptional targets not identified
    • Did not distinguish cell-autonomous from non-autonomous effects
  2. 1997 High

    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

    PMID:9187081 PMID:9188040 PMID:9247261 PMID:9428417

    Open questions at the time
    • Mechanism of redundancy with Dlx1 not resolved at the molecular level
    • No direct target genes defined
  3. 2000 Medium

    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

    PMID:10603340

    Open questions at the time
    • Direct vs indirect transcriptional inputs not separated
    • Regulatory elements mapped only coarsely
  4. 2001 Medium

    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

    PMID:11445007 PMID:11763998

    Open questions at the time
    • Endogenous occupancy of the bicoid elements not shown by ChIP
    • In vivo relevance of PITX2/Msx2 antagonism untested
  5. 2004 High

    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

    PMID:15604100

    Open questions at the time
    • Direct targets in RGCs not yet identified
    • Cause of ectopic Crx expression unresolved
  6. 2005 Medium

    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

    PMID:15848386

    Open questions at the time
    • Adhesion genes not shown to be direct targets
    • Mechanism of migration arrest unknown
  7. 2006 High

    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

    PMID:16705037

    Open questions at the time
    • Structural basis of Evf-2/DLX-2 binding unknown
    • Generality to other Dlx targets untested
  8. 2007 High

    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

    PMID:17068080 PMID:17678855 PMID:18086710

    Open questions at the time
    • Genome-wide target set not defined
    • How DLX2 switches between activation and repression unclear
  9. 2008 High

    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

    PMID:18562615 PMID:18923043 PMID:19026749 PMID:22699903

    Open questions at the time
    • Arx separates migration from fate commitment but the fate-commitment effector is unidentified
    • Coupling of cell cycle exit to differentiation not fully mechanistic
  10. 2009 Medium

    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

    PMID:19683576

    Open questions at the time
    • Direct transcriptional targets in proliferation control unknown
    • In vivo requirement not established here
  11. 2011 Medium

    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

    PMID:21897365 PMID:21917150

    Open questions at the time
    • Direct binding to TGFbetaRII promoter shown only by reporter assays
    • Mechanism of ROS-dependent induction undefined
  12. 2015 Medium

    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

    PMID:25651912 PMID:26771232

    Open questions at the time
    • Snail and GLS1 not shown to be direct DLX2 transcriptional targets
    • Cancer-type generality untested
  13. 2016 Medium

    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

    PMID:26799321 PMID:26833729 PMID:28459464

    Open questions at the time
    • Basis for opposite pro-apoptotic vs pro-survival outputs unresolved
    • Mechanism of TTI/TEL2 destabilization not defined
  14. 2019 High

    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

    PMID:29787757 PMID:30880332 PMID:32165291

    Open questions at the time
    • Interplay with canonical osteogenic factors (Runx2/Osterix) left unaffected and unexplained
    • Coordination of activator vs repressor target selection unknown
  15. 2023 Medium

    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

    PMID:37286519

    Open questions at the time
    • Direct recruitment of JMJD3 to the locus not shown
    • Relevance beyond the aneurysm context unclear
  16. 2026 High

    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

    PMID:41533791

    Open questions at the time
    • Genome-wide pioneering target catalogue not defined
    • Whether LAP2alpha partnership operates in non-craniofacial DLX2 functions unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 5 GO:0003723 RNA binding 1
Localization
GO:0005634 nucleus 4
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 3 R-HSA-4839726 Chromatin organization 2
Partners
EVF-2LAP2ALPHALEF-1PAX6TAF15

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 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. In vivo co-immunoprecipitation (stable Evf-2/DLX-2 complex), reporter/transcription assays, RNA-protein interaction studies Genes & development High 16705037
1995 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. Gene targeting (null mutation), histological and skeletal phenotype analysis in homozygous mutant mice Genes & development High 7590232
1997 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. Double knockout mouse, histological and marker analysis of striatal phenotype Neuron High 9247261
1997 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. Double knockout mouse, heterologous tissue recombination, molecular marker analysis (Barx1, Sox9) Development (Cambridge, England) High 9428417
1997 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. Antisense oligonucleotide knockdown in primary cultures, MAP2 immunostaining, cell proliferation assays Journal of molecular neuroscience Medium 9188040
1997 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. Single and double knockout mouse models, skeletal and soft tissue analysis Developmental biology High 9187081
2000 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. Transgenic reporter (lacZ) analysis, signaling factor treatment of explants, regulatory element mapping Development (Cambridge, England) Medium 10603340
2001 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. Antisense oligonucleotide knockdown, dominant-negative Smad1, Col2alpha1 enhancer reporter assays DNA and cell biology Medium 11445007
2001 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. Luciferase reporter assays, EMSA (electrophoretic mobility shift assay), RT-PCR, Western blot Gene expression Medium 11763998
2004 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. Double knockout mouse, histological and marker analysis of retinal phenotype, TUNEL apoptosis assay Development (Cambridge, England) High 15604100
2005 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. In ovo electroporation, immunostaining for N-cadherin and NCAM, cell migration assay Developmental biology Medium 15848386
2006 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. ChIP, co-immunoprecipitation, protein pull-down, luciferase reporter assays, deletion analysis Nucleic acids research High 17068080
2007 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. Double knockout mouse, progenitor transplantation into wild-type host, myelination/marker analysis Neuron High 17678855
2007 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. ChIP, luciferase reporter assay, ectopic expression in retinal explants, siRNA knockdown in primary cultures Nucleic acids research High 18086710
2008 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. Retroviral cell-autonomous loss-of-function, genetic epistasis (Pax6 conditional knockout), immunostaining of neuronal subtypes The Journal of neuroscience High 18562615
2008 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. Gain-of-function (Dlx overexpression), loss-of-function (Dlx/Arx mutants), enhancer reporter assay, genetic epistasis The Journal of neuroscience High 18923043
2008 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. Rb knockout mouse, ChIP, in vitro reporter assays, interneuron subtype and migration analysis The Journal of neuroscience High 22699903
2008 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. Cre-transgenic mice, fate mapping (Z/EG reporter), Dlx1/2 mutant analysis, enhancer activity assays Molecular and cellular neurosciences Medium 19026749
2009 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. Forced DLX2 expression in SVZ-isolated NSCs, in vitro proliferation and lineage assays, EGF response measurement Molecular and cellular neurosciences Medium 19683576
2011 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. shRNA knockdown, propidium iodide staining, HMGB1/LDH release assay, mitochondrial ROS measurement Molecular cancer Medium 21917150
2011 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. Reporter assays, Western blot, gene expression analysis, overexpression/knockdown in mammary epithelial cells The EMBO journal Medium 21897365
2015 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. shRNA knockdown, gene expression analysis, Western blot, pathway perturbation with TGF-β/Wnt in cancer cell lines International journal of oncology Medium 25651912
2016 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. shRNA knockdown, pharmacological inhibitors, gene expression analysis, in vivo metastasis assay Oncotarget Medium 26771232
2016 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. Gain-of-function screen, protein complex component analysis, ATM-p53 signaling assays, replicative lifespan measurement Genes & development Medium 26833729
2016 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. siRNA knockdown, DLX2 overexpression, Smad2/3 knockdown, colony formation assay, migration/invasion assays in cancer cell lines PloS one Medium 26799321
2017 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. siRNA knockdown, VPA treatment, Smad phosphorylation analysis, orthotopic mouse transplantation model Oncogene Medium 28459464
2017 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. Triple knockout mouse, Dlx2 knockdown in primary cultures, in utero gain-of-function, marker and cell-fate analysis Development (Cambridge, England) High 28356311
2018 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. Conditional knockout (Dlx1, Dlx2, Dlx1&2 CKOs), electrophysiology (mIPSC), immunostaining, gene expression analysis Cerebral cortex High 29028947
2019 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. ChIP assay, site-directed mutagenesis, luciferase reporter assay, ALP activity, Alizarin red staining, in vivo implantation in nude mice International journal of oral science High 30880332
2020 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. ChIP assay, reporter assay (implied), Western blot, ALP activity, Alizarin red staining, β-catenin inhibitor rescue Gene Medium 32165291
2021 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. Dlx2 misexpression in OPCs, transcriptome analysis, electrophysiology, immunostaining of synaptic markers Scientific reports High 33574458
2018 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. Dlx2 overexpression, luciferase reporter assay, ChIP, Western blot, qRT-PCR Biochemical and biophysical research communications High 29787757
2023 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. siRNA knockdown of JMJD3 and DLX2, H3K27me3 chromatin analysis, rescue overexpression, in vivo model The Tohoku journal of experimental medicine Medium 37286519
2026 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. ESC differentiation assay, co-immunoprecipitation (DLX2-LAP2α complex), domain mutagenesis, chromatin remodeling assays, scRNA-seq trajectory analysis Science advances High 41533791
2025 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. Single-cell whole genome spatial transcriptomics, multi-omic approach, DLX2 regulatory network analysis in ventral telencephalon bioRxivpreprint Medium
2022 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. RNA immunoprecipitation (RIP), RNA pulldown, Western blot, ALP activity, Alizarin red staining Experimental cell research Medium 35644412

Source papers

Stage 0 corpus · 95 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 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. The Journal of comparative neurology 760 10906711
2006 The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator. Genes & development 574 16705037
1993 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. The Journal of neuroscience : the official journal of the Society for Neuroscience 523 7687285
1997 Mutations of the homeobox genes Dlx-1 and Dlx-2 disrupt the striatal subventricular zone and differentiation of late born striatal neurons. Neuron 443 9247261
1997 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. Developmental biology 389 9187081
1995 Null mutation of Dlx-2 results in abnormal morphogenesis of proximal first and second branchial arch derivatives and abnormal differentiation in the forebrain. Genes & development 321 7590232
2007 Dlx1 and Dlx2 control neuronal versus oligodendroglial cell fate acquisition in the developing forebrain. Neuron 294 17678855
1999 DLX-1, DLX-2, and DLX-5 expression define distinct stages of basal forebrain differentiation. The Journal of comparative neurology 237 10516593
1994 Differential and overlapping expression domains of Dlx-2 and Dlx-3 suggest distinct roles for Distal-less homeobox genes in craniofacial development. Mechanisms of development 217 7893603
1997 Role of Dlx-1 and Dlx-2 genes in patterning of the murine dentition. Development (Cambridge, England) 198 9428417
1993 The mouse Dlx-2 (Tes-1) gene is expressed in spatially restricted domains of the forebrain, face and limbs in midgestation mouse embryos. Mechanisms of development 194 8098616
1994 DLX-2, MASH-1, and MAP-2 expression and bromodeoxyuridine incorporation define molecularly distinct cell populations in the embryonic mouse forebrain. The Journal of neuroscience : the official journal of the Society for Neuroscience 185 7965042
2008 A dlx2- and pax6-dependent transcriptional code for periglomerular neuron specification in the adult olfactory bulb. The Journal of neuroscience : the official journal of the Society for Neuroscience 164 18562615
2008 Arx is a direct target of Dlx2 and thereby contributes to the tangential migration of GABAergic interneurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 120 18923043
2002 Subpallial dlx2-expressing cells give rise to astrocytes and oligodendrocytes in the cerebral cortex and white matter. The Journal of neuroscience : the official journal of the Society for Neuroscience 93 12427838
2008 Generation of Cre-transgenic mice using Dlx1/Dlx2 enhancers and their characterization in GABAergic interneurons. Molecular and cellular neurosciences 90 19026749
2007 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. The Journal of neuroscience : the official journal of the Society for Neuroscience 87 17494687
2000 Independent regulation of Dlx2 expression in the epithelium and mesenchyme of the first branchial arch. Development (Cambridge, England) 87 10603340
2019 Overexpression of Dlx2 enhances osteogenic differentiation of BMSCs and MC3T3-E1 cells via direct upregulation of Osteocalcin and Alp. International journal of oral science 73 30880332
2018 Dlx1 and Dlx2 Promote Interneuron GABA Synthesis, Synaptogenesis, and Dendritogenesis. Cerebral cortex (New York, N.Y. : 1991) 73 29028947
1996 Sequence, organization, and transcription of the Dlx-1 and Dlx-2 locus. Genomics 71 8812481
2016 Dlx-2 and glutaminase upregulate epithelial-mesenchymal transition and glycolytic switch. Oncotarget 68 26771232
2004 Dlx1 and Dlx2 function is necessary for terminal differentiation and survival of late-born retinal ganglion cells in the developing mouse retina. Development (Cambridge, England) 67 15604100
2001 Antagonistic regulation of Dlx2 expression by PITX2 and Msx2: implications for tooth development. Gene expression 62 11763998
2011 Transcription factor Dlx2 protects from TGFβ-induced cell-cycle arrest and apoptosis. The EMBO journal 55 21897365
2001 A zebrafish forebrain-specific zinc finger gene can induce ectopic dlx2 and dlx6 expression. Developmental biology 43 11180958
2001 Bone morphogenetic protein-2 (BMP-2) signaling to the Col2alpha1 gene in chondroblasts requires the homeobox gene Dlx-2. DNA and cell biology 43 11445007
1995 Regionalization of the developing forebrain: a comparison of FORSE-1, Dlx-2, and BF-1. The Journal of neuroscience : the official journal of the Society for Neuroscience 42 7869122
2012 The Rb/E2F pathway modulates neurogenesis through direct regulation of the Dlx1/Dlx2 bigene cluster. The Journal of neuroscience : the official journal of the Society for Neuroscience 41 22699903
2004 Cloning and developmental expression patterns of Dlx2, Lhx7 and Lhx9 in the medaka fish (Oryzias latipes). Mechanisms of development 41 15210202
2017 Mutant Runx2 regulates amelogenesis and osteogenesis through a miR-185-5p-Dlx2 axis. Cell death & disease 40 29242628
2010 Mutually exclusive expression of DLX2 and DLX5/6 is associated with the metastatic potential of the human breast cancer cell line MDA-MB-231. BMC cancer 40 21108812
2009 Interaction between DLX2 and EGFR regulates proliferation and neurogenesis of SVZ precursors. Molecular and cellular neurosciences 39 19683576
2003 Dlx2 progenitor migration in wild type and Nkx2.1 mutant telencephalon. Cerebral cortex (New York, N.Y. : 1991) 39 12902388
2016 KI67 and DLX2 predict increased risk of metastasis formation in prostate cancer-a targeted molecular approach. British journal of cancer 37 27336609
2020 Long non-coding RNA TUG1 promotes cell progression in hepatocellular carcinoma via regulating miR-216b-5p/DLX2 axis. Cancer cell international 36 31920462
1992 DLX2 (TES1), a homeobox gene of the Distal-less family, assigned to conserved regions on human and mouse chromosomes 2. Genomics 35 1354641
2020 ASCL1- and DLX2-induced GABAergic neurons from hiPSC-derived NPCs. Journal of neuroscience methods 34 32065989
2015 Dlx-2 is implicated in TGF-β- and Wnt-induced epithelial-mesenchymal, glycolytic switch, and mitochondrial repression by Snail activation. International journal of oncology 34 25651912
2012 Dynamic expression of the pro-dopaminergic transcription factors Pax6 and Dlx2 during postnatal olfactory bulb neurogenesis. Frontiers in cellular neuroscience 34 22371698
2006 OY-TES-1 expression and serum immunoreactivity in epithelial ovarian cancer. International journal of oncology 34 16964386
2017 Bone morphogenetic protein signaling mediated by ALK-2 and DLX2 regulates apoptosis in glioma-initiating cells. Oncogene 33 28459464
2000 Biomineralization, life-time of odontogenic cells and differential expression of the two homeobox genes MSX-1 and DLX-2 in transgenic mice. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 32 10750557
2017 Regulation of Brn3b by DLX1 and DLX2 is required for retinal ganglion cell differentiation in the vertebrate retina. Development (Cambridge, England) 28 28356311
2005 Dlx2 over-expression regulates cell adhesion and mesenchymal condensation in ectomesenchyme. Developmental biology 28 15848386
1995 The spatial localization of Dlx-2 during tooth development. Connective tissue research 28 7554927
2016 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. PloS one 27 26799321
2013 Increased expression of DLX2 correlates with advanced stage of gastric adenocarcinoma. World journal of gastroenterology 26 23674878
2006 Functional interactions between Dlx2 and lymphoid enhancer factor regulate Msx2. Nucleic acids research 26 17068080
2003 Dlx-1 and Dlx-2 expression in the adult mouse brain: relationship to dopaminergic phenotypic regulation. The Journal of comparative neurology 26 12722102
2010 Role of Dlx genes in craniofacial morphogenesis: Dlx2 influences skeletal patterning by inducing ectomesenchymal aggregation in ovo. Evolution & development 25 20883215
2020 Knockdown of circ_HIPK3 inhibits tumorigenesis of hepatocellular carcinoma via the miR-582-3p/DLX2 axis. Biochemical and biophysical research communications 23 32977948
2011 Homeobox gene Dlx-2 is implicated in metabolic stress-induced necrosis. Molecular cancer 23 21917150
2012 The effect of overexpression of Dlx2 on the migration, proliferation and osteogenic differentiation of cranial neural crest stem cells. Biomaterials 22 23246068
2016 A gain-of-function senescence bypass screen identifies the homeobox transcription factor DLX2 as a regulator of ATM-p53 signaling. Genes & development 21 26833729
2013 Cancer testis antigen OY-TES-1 expression and serum immunogenicity in colorectal cancer: its relationship to clinicopathological parameters. International journal of clinical and experimental pathology 21 24294369
2020 DLX2 activates Wnt1 transcription and mediates Wnt/β-catenin signal to promote osteogenic differentiation of hBMSCs. Gene 20 32165291
2021 Direct reprogramming of oligodendrocyte precursor cells into GABAergic inhibitory neurons by a single homeodomain transcription factor Dlx2. Scientific reports 19 33574458
2019 Actinidia Chinensis Planch Root extract attenuates proliferation and metastasis of hepatocellular carcinoma by inhibiting the DLX2/TARBP2/JNK/AKT pathway. Journal of ethnopharmacology 19 31891797
2007 GAD isoforms exhibit distinct spatiotemporal expression patterns in the developing mouse lens: correlation with Dlx2 and Dlx5. Developmental dynamics : an official publication of the American Association of Anatomists 19 17969168
2007 Dlx2 homeobox gene transcriptional regulation of Trkb neurotrophin receptor expression during mouse retinal development. Nucleic acids research 19 18086710
2019 Expression of ventral telencephalon transcription factors ASCL1 and DLX2 in the early fetal human cerebral cortex. Journal of anatomy 18 30861584
2011 Up-regulation of homeodomain genes, DLX1 and DLX2, by FLT3 signaling. Haematologica 18 21357706
2004 Identification and characterization of a novel transcript down-regulated in Dlx1/Dlx2 and up-regulated in Pax6 mutant telencephalon. Developmental dynamics : an official publication of the American Association of Anatomists 18 15376329
2005 Identification of an HLA-A24-restricted OY-TES-1 epitope recognized by cytotoxic T-cells. Microbiology and immunology 17 16301813
2012 Knockdown of OY-TES-1 by RNAi causes cell cycle arrest and migration decrease in bone marrow-derived mesenchymal stem cells. Cell biology international 16 22651134
1997 Dlx-2 homeobox gene controls neuronal differentiation in primary cultures of developing basal ganglia. Journal of molecular neuroscience : MN 16 9188040
1993 The human brain homeogene, DLX-2: cDNA sequence and alignment with the murine homologue. Gene 16 7901126
2015 Down-regulation of cancer/testis antigen OY-TES-1 attenuates malignant behaviors of hepatocellular carcinoma cells in vitro. International journal of clinical and experimental pathology 15 26339343
2017 Serum immunoreactivity of cancer/testis antigen OY-TES-1 and its tissues expression in glioma. Oncology letters 14 28529561
2018 Dlx2 overexpression enhanced accumulation of type II collagen and aggrecan by inhibiting MMP13 expression in mice chondrocytes. Biochemical and biophysical research communications 13 29787757
2022 LncRNA HOTTIP facilitates osteogenic differentiation in bone marrow mesenchymal stem cells and induces angiogenesis via interacting with TAF15 to stabilize DLX2. Experimental cell research 12 35644412
2011 Proneural transcription factors Dlx2 and Pax6 are altered in adult SVZ neural precursor cells following striatal cell loss. Molecular and cellular neurosciences 12 21397028
2021 Repeated Irradiation with γ-Ray Induces Cancer Stemness through TGF-β-DLX2 Signaling in the A549 Human Lung Cancer Cell Line. International journal of molecular sciences 11 33924205
2015 Effects of DLX2 overexpression on the osteogenic differentiation of MC3T3-E1 cells. Experimental and therapeutic medicine 10 26136955
2020 Cancer-testis Antigen OY-TES-1 Expression and Immunogenicity in Hepatocellular Carcinoma. Current medical science 9 32862383
2022 TES-1/Tes and ZYX-1/Zyxin protect junctional actin networks under tension during epidermal morphogenesis in the C. elegans embryo. Current biology : CB 7 36384139
2017 Dental and periodontal phenotypes of Dlx2 overexpression in mice. Molecular medicine reports 7 28447749
2024 Efficient Dlx2-mediated astrocyte-to-neuron conversion and inhibition of neuroinflammation by NeuroD1. Developmental neurobiology 6 39034481
2023 GABAergic neurons differentiated from BDNF- and Dlx2-modified neural stem cells restore disrupted neural circuits in brainstem stroke. Stem cell research & therapy 6 37365654
2022 A Neural Crest-specific Overexpression Mouse Model Reveals the Transcriptional Regulatory Effects of Dlx2 During Maxillary Process Development. Frontiers in physiology 6 35514355
2024 Osteocyte-derived exosomes regulate the DLX2/wnt pathway to alleviate osteoarthritis by mediating cartilage repair. Autoimmunity 5 38946534
2024 Characteristic changes in astrocyte properties during astrocyte-to-neuron conversion induced by NeuroD1/Ascl1/Dlx2. Neural regeneration research 4 39104117
2023 JMJD3 is Involved in Intracranial Aneurysm Development by Regulating DLX2 Expression through H3K27me3 Modification. The Tohoku journal of experimental medicine 2 37286519
2022 Immunohistochemistry Study of OY-TES-1 Location in Fetal and Adult Human Tissues. Journal of healthcare engineering 2 35463688
2016 Overexpression of Dlx2 leads to postnatal condyle degradation. Molecular medicine reports 2 27315306
1999 Establishment and characterization of human immature teratoma cell line (TES-1). Anticancer research 2 10470137
2023 Effects of Dlx2 overexpression on the genes associated with the maxillary process in the early mouse embryo. Frontiers in genetics 1 36891149
2026 DLX2 acts as a pioneer factor and drives Msx1+ ectomesenchyme formation from embryonic stem cells. Science advances 0 41533791
2026 DLX2 marks an immunosuppressive dendritic-cell program that reshapes cytotoxic immunity and marks a tolerogenic microenvironment in lung adenocarcinoma. Discover oncology 0 41761000
2026 PTTG1-DLX2 axis drives malignant progression of lung adenocarcinoma by activating the WNT/β-catenin signaling pathway. Translational cancer research 0 42180979
2025 DLX2 promotes gastric cancer epithelial- mesenchymal transition and malignant progression through the PI3K/AKT signaling pathway. Frontiers in oncology 0 41244921
2025 OY-TES-1 Splice Variant V5a in Glioma: A Driver of Malignancy and Potential Therapeutic Target. Current medical science 0 41428155
2011 Dlx2 over-expression: a possible mechanism for first branchial arch malformation. Shanghai kou qiang yi xue = Shanghai journal of stomatology 0 21779750
2003 [Expression of homeobox gene Msx-1, Msx-2 and Dlx-2 during murine mandibular first molar development]. Zhonghua kou qiang yi xue za zhi = Zhonghua kouqiang yixue zazhi = Chinese journal of stomatology 0 14703475

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