Affinage

DLX5

Homeobox protein DLX-5 · UniProt P56178

Length
289 aa
Mass
31.5 kDa
Annotated
2026-06-09
100 papers in source corpus 43 papers cited in narrative 42 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DLX5 is a homeodomain transcription factor that serves as a central effector of skeletal, craniofacial, and neural development, transducing BMP signaling into osteogenic and patterning gene programs (PMID:12815054, PMID:10433909, PMID:10433912). In the osteoblast lineage, BMP-2 immediately and protein-synthesis-independently induces Dlx5, which acts as an obligatory upstream mediator of both Runx2 and Osterix and is itself required for osteoblast differentiation (PMID:12815054, PMID:12963046). DLX5 exerts this control by directly binding homeodomain elements: three response elements in the Runx2 type II (P1) promoter, the proximal Osterix promoter, a cis-element in the alkaline phosphatase promoter, and an osteoblast-specific Runx2 enhancer where it cooperates with Mef2c to nucleate an enhanceosome (PMID:16115867, PMID:18056716, PMID:15383550, PMID:24692107). At the osteocalcin promoter DLX5 antagonizes MSX2-mediated repression, both by competing for shared homeodomain elements and by forming inhibitory heterodimers with MSX2 through residues 127–143, and a developmental switch recruits DLX5 to activate the gene postproliferatively (PMID:16115867, PMID:15383550, PMID:9819228, PMID:15456894). DLX5 transcriptional output is tuned post-translationally by p38 MAPK phosphorylation at Ser-34/Ser-217 and by CaMKII, which enhance transactivation and stability, and by the Dlxin-1 co-activator whose abundance is controlled by the E3 ligase Praja1 (PMID:18056716, PMID:19393622, PMID:11084035, PMID:11959851). In craniofacial development DLX5/6 specify mandibular identity, regulate chondrocyte hypertrophy cell-autonomously, and operate within Hand2 negative-feedback and FGF-mediated mesenchymal circuits (PMID:12434331, PMID:19956613, PMID:21558373, PMID:28982687). Long-range DLX5/6 intergenic enhancers (I56i) are bound and cross-activated by DLX proteins, and combined Dlx5/6 loss produces split-hand/split-foot malformation with limb defects rescuable by AER-restricted Dlx5 (PMID:10632600, PMID:12000792). In the nervous system DLX5 is cell-autonomously required for parvalbumin-positive cortical interneuron development, postnatal neurogenesis, and olfactory neuron axon targeting (PMID:20392955, PMID:14962748, PMID:12533617). In cancer, DLX5 directly activates MYC and IRS-2 to drive proliferation and AKT signaling (PMID:19497851, PMID:21045156).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1998 High

    Established that DLX5 functions partly through protein-protein interaction rather than solely DNA binding, by showing it heterodimerizes with MSX2 to relieve repression of osteocalcin.

    Evidence Far-Western, deletion/structure-function mapping and reporter assays identifying residues 127–143

    PMID:9819228

    Open questions at the time
    • Did not map the MSX2 interaction surface
    • OCFREB de-repression mechanism not structurally defined
  2. 1999 High

    Defined the in vivo requirement for Dlx5, showing it is independently needed for branchial arch patterning, vestibular morphogenesis, and osteoblast differentiation.

    Evidence Dlx5-null mouse with phenotypic analysis, independently replicated

    PMID:10433909 PMID:10433912

    Open questions at the time
    • Did not identify direct transcriptional targets underlying each phenotype
    • Functional redundancy with Dlx6 not resolved
  3. 2002 High

    Placed Dlx5/6 at the top of jaw and limb identity programs through combinatorial loss-of-function and spatially restricted rescue.

    Evidence Dlx5/6 double-knockout mice with mandibular-to-maxillary transformation and AER-restricted transgenic rescue of limb defects

    PMID:12000792 PMID:12434331

    Open questions at the time
    • Direct targets specifying mandibular identity not enumerated
    • Mechanism of split-hand/foot phenotype not molecularly resolved here
  4. 2003 High

    Identified Dlx5 as the indispensable, immediate BMP-2 effector upstream of both Runx2 and Osterix, ordering the osteogenic transcription cascade.

    Evidence Cycloheximide, antisense Dlx5 blocking and overexpression in C2C12 cells with BMP-2/TGF-β1 treatment

    PMID:12815054 PMID:12963046

    Open questions at the time
    • Did not show direct promoter binding (addressed later)
    • Mechanism of immediate BMP-2 induction of Dlx5 not defined
  5. 2005 High

    Demonstrated direct, sequence-specific DLX5 transactivation of Runx2 type II and competitive antagonism by MSX2, providing the cis-regulatory basis for the cascade.

    Evidence Runx2 promoter deletion, EMSA, site-directed mutagenesis of three homeodomain elements, Dlx5/Msx2 overexpression

    PMID:16115867

    Open questions at the time
    • In vivo enhancer context not tested here (later addressed)
    • Stoichiometry of Dlx5/Msx2 competition not quantified
  6. 2007 High

    Showed that DLX5 osteogenic activity is gated by signaling, with p38 MAPK directly phosphorylating Ser-34/Ser-217 to boost transactivation and Osterix expression.

    Evidence In vitro/in vivo kinase assays, phosphosite mutagenesis, EMSA and ChIP at Osterix promoter

    PMID:18056716

    Open questions at the time
    • Structural consequence of phosphorylation not defined
    • Whether CaMKII and p38 act on same residues unknown
  7. 2004 High

    Revealed a co-activator/degradation module tuning DLX5 output via Dlxin-1 and its turnover, and a chromatin-level repression mechanism at the locus via MeCP2.

    Evidence Y2H/GST/Co-IP and ubiquitination assays for Dlxin-1–Praja1; ChIP-loop assays for MeCP2/HDAC1/H3K9me at the Dlx5–Dlx6 locus in Mecp2-null brain

    PMID:11084035 PMID:11959851 PMID:15608638

    Open questions at the time
    • Physiological contexts where Dlxin-1/Praja1 set DLX5 levels not defined
    • Whether MeCP2 silencing operates outside brain unknown
  8. 2004 High

    Resolved DLX5 as a Runx2-independent activator of differentiation markers and established its cell-autonomous role in postnatal neurogenesis.

    Evidence EMSA/mutagenesis at the ALP promoter in Runx2-null cells; Dlx5-null neural stem cell cultures with re-expression rescue

    PMID:14962748 PMID:15383550

    Open questions at the time
    • Downstream neuronal differentiation targets of DLX5 not identified
    • ALP activation cofactors not defined
  9. 2010 High

    Extended DLX5 function to interneuron specification and cancer, showing cell-autonomous control of parvalbumin interneurons and direct activation of MYC and IRS-2 in tumors.

    Evidence Interneuron transplantation/conditional deletion; EMSA/ChIP and rescue for MYC (lung) and IRS-2/AKT (ovarian) in tumor models

    PMID:19497851 PMID:20392955 PMID:21045156

    Open questions at the time
    • How DLX5 is reactivated in cancer not defined here
    • Interneuron target genes not identified
  10. 2014 High

    Established the in vivo enhanceosome basis of DLX5-driven osteoblast Runx2 expression and connected DLX5 to AER stratification through an FGF8-Pin1-p63 loop.

    Evidence BAC-GFP reporter mice with binding-site mutagenesis (Dlx5/Mef2c Runx2 enhancer); ChIP and Pin1/p63 interaction analysis for FGF8 loop

    PMID:24569166 PMID:24692107

    Open questions at the time
    • Order of enhanceosome assembly not resolved
    • FGF8-Pin1-p63 loop is single-lab Medium evidence
  11. 2011 Medium

    Defined the Hand2 negative-feedback architecture and FGF-mediated mesenchymal circuits through which Dlx5 patterns the mandibular arch and palate.

    Evidence Conditional knockouts and double-knockout epistasis with Fgf7/Fgf10/Shh rescue experiments

    PMID:19934017 PMID:21558373 PMID:28982687

    Open questions at the time
    • Direct vs indirect regulation of some FGF ligands not fully separated
    • Single-lab epistasis for several circuits
  12. 2018 Medium

    Identified upstream repressive inputs (STAT5A, cAMP/PKA-CREB-C/EBPβ) that set Dlx5 levels and bias osteogenic vs adipogenic fate.

    Evidence STAT5A knockout/knockdown with micro-CT; cAMP/PKA epistasis with ChIP for C/EBPβ at the Dlx5 promoter

    PMID:30322210 PMID:30429452

    Open questions at the time
    • Single-lab studies
    • Integration of multiple repressive inputs not modeled
  13. 2021 Medium

    Showed DLX5 acts within a TP63/SOX2 oncogenic enhancer network in squamous cell carcinoma, broadening its cancer role beyond single-gene activation.

    Evidence ChIP-seq for DLX5/TP63, SOX2 ChIP, bisulfite sequencing, and shRNA knockdown in vitro and in xenografts

    PMID:34370013

    Open questions at the time
    • Single-lab study
    • Mechanism coupling SOX2-driven DLX5 to specific oncogenic outputs not fully defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DLX5's distinct post-translational modifications, cofactor states, and partner choices are integrated to select among osteogenic, chondrogenic, neural, and oncogenic gene programs in a given cell remains unresolved.
  • No unified model linking phosphorylation state to target selectivity
  • Genome-wide DLX5 occupancy compared across tissues not established
  • Structural basis of MSX2/HOXC8 heterodimer specificity unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 5 GO:0140110 transcription regulator activity 5
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4
Partners
DLXIN-1HOXC8MEF2CMSX1MSX2TP63
Complex memberships
Runx2 osteoblast enhanceosome (Dlx5/Mef2c)

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 MeCP2 mediates formation of a silent-chromatin loop at the Dlx5-Dlx6 locus by recruiting histone deacetylase 1 and promoting repressive histone methylation at Lys9, thereby suppressing Dlx5 transcription; loss of MeCP2 abolishes this loop and increases Dlx5-Dlx6 expression approximately two-fold in mouse brain. Chromatin immunoprecipitation combined loop assays, ChIP for HDAC1 and H3K9 methylation, Mecp2-null mouse brains Nature genetics High 15608638
1999 Targeted null mutation of Dlx5 in mice causes craniofacial abnormalities (derivatives of branchial arches 1–4), severe malformations of the vestibular organ, delayed ossification of the skull roof, and abnormal osteogenesis, establishing independent roles for Dlx5 in branchial arch patterning, vestibular morphogenesis, and osteoblast differentiation. Gene targeting (Dlx5 null allele replacing exons I and II with lacZ), phenotypic analysis of homozygous mutant mice Development (Cambridge, England) High 10433909 10433912
2003 BMP-2 specifically and immediately induces Dlx5 expression (independent of new protein synthesis), and Dlx5 is an indispensable upstream mediator of BMP-2-induced Runx2 expression and osteoblast differentiation; TGF-β1 opposes this pathway by inducing AP-1, which suppresses Dlx5 expression. Cycloheximide treatment, antisense Dlx5 blocking, overexpression assays in C2C12 cells, BMP-2/TGF-β1 treatment The Journal of biological chemistry High 12815054
2003 BMP-2-induced Osterix expression requires Dlx5 as an obligatory upstream mediator; antisense blocking of Dlx5 completely abrogates BMP-2-induced Osterix expression, whereas Runx2 overexpression alone is insufficient to induce Osterix in myogenic cells. Antisense Dlx5 blocking, Runx2 null cells, Runx2 overexpression in C2C12, BMP-2 treatment Biochemical and biophysical research communications High 12963046
2007 Dlx5 binds to homeodomain sequences in the proximal Osterix promoter both in vitro and in vivo. Additionally, Dlx5 is a direct substrate of p38 MAPK, which phosphorylates Dlx5 at Ser-34 and Ser-217; this phosphorylation increases the transactivation potential of Dlx5 and enhances Osterix expression. In vitro kinase assay, in vivo phosphorylation assay, EMSA, ChIP, site-directed mutagenesis of phosphorylation sites, Dlx5 overexpression/knockdown The Journal of biological chemistry High 18056716
2005 Dlx5 specifically transactivates the Runx2 type II (P1 distal promoter) by directly binding to three homeodomain-response elements between -756 and -342 bp of the P1 promoter, as confirmed by gel mobility shift assay and site-directed mutagenesis; Msx2 antagonizes this by competing for the same elements. Runx2 promoter deletion analysis, gel mobility shift assay (EMSA), site-directed mutagenesis, overexpression of Dlx5 and Msx2, in situ hybridization in developing cranial vault The Journal of biological chemistry High 16115867
2004 Dlx5 directly binds to a cis-acting homeodomain element in the alkaline phosphatase (ALP) promoter to stimulate ALP expression independently of Runx2; Msx2 competes with Dlx5 for this same element to repress ALP transcription. EMSA, site-directed mutagenesis, ALP promoter reporter assays, Runx2-null cell studies, Dlx5/Msx2 overexpression The Journal of biological chemistry High 15383550
1998 Dlx5 reverses Msx2-mediated repression of the osteocalcin promoter by forming heterodimers with Msx2 via residues 127–143 of Dlx5; intrinsic DNA binding by Dlx5 is not required for this de-repression, which instead involves abrogating Msx2 inhibition of the OCFREB transcription factor. Far-Western blot (protein-protein interaction), transient cotransfection reporter assays, deletion/structure-function analysis, EMSA Biochemistry High 9819228
2001 Dlx5 interferes with the ability of Msx2 to interact with Runx2 and to repress Runx2 transcriptional activity; the craniosynostosis-associated Msx2 P148H mutant retains ability to bind and repress Runx2 but is resistant to Dlx5 regulation. Co-immunoprecipitation, transcriptional reporter assays, overexpression of Dlx5 and Msx2 mutants in C2C12 cells Genes to cells : devoted to molecular & cellular mechanisms Medium 11683913
2004 Chromatin immunoprecipitation in osteoblasts revealed a sequential switch in homeodomain protein occupancy at the osteocalcin gene promoter: Msx2 occupies the repressed promoter in proliferating osteoblasts, then Dlx3 and Dlx5 are recruited postproliferatively to activate transcription, with Dlx5 occupancy increasing over Dlx3 at the mineralization stage; Dlx5 occupies the OC promoter coincident with increased RNA polymerase II. Chromatin immunoprecipitation (ChIP) assays, RNA interference knockdown of Dlx3, reporter assays, Dlx3-Runx2 protein-protein interaction mapping Molecular and cellular biology High 15456894
2002 Dlxin-1, a novel MAGE/necdin-related protein, physically binds Dlx5 (also Dlx7 and Msx2) and activates the transcriptional function of Dlx5 in reporter assays. Yeast two-hybrid screening, GST pull-down, co-immunoprecipitation, reporter gene assays The Journal of biological chemistry Medium 11084035
2002 The RING finger E3 ubiquitin ligase Praja1 binds Dlxin-1 (a Dlx5-interacting protein) and promotes its ubiquitin-dependent proteasomal degradation, thereby down-regulating Dlx5-dependent transcriptional activity; a RING finger mutant of Praja1 lacks these effects. Yeast two-hybrid, GST pull-down, co-immunoprecipitation, in vivo ubiquitination assay, proteasome inhibitor treatment, GAL4-dependent transcription reporter assay, RING finger mutagenesis The Journal of biological chemistry High 11959851
2002 Combined targeted inactivation of Dlx5 and Dlx6 results in homeotic-like transformation of the lower jaw into an upper jaw structure, demonstrating that Dlx5/6 specify mandibular (lower jaw) identity in the first pharyngeal arch. Double knockout mice (Dlx5 and Dlx6 null alleles), skeletal morphological analysis Genesis (New York, N.Y. : 2000) High 12434331
2002 Combined null mutation of Dlx5 and Dlx6 causes severe craniofacial, axial, and appendicular skeletal abnormalities including split-hand/split-foot malformation (ectrodactyly); transgenic overexpression of Dlx5 specifically in the apical ectodermal ridge of Dlx5/6 null mice fully rescues limb outgrowth defects. Double knockout mice, spatiotemporal transgenic rescue, skeletal analysis Genes & development High 12000792
2002 Dlx5 is a positive regulator of chondrocyte maturation; retroviral misexpression of Dlx5 in the chick limb promotes conversion of immature proliferating chondrocytes into hypertrophying chondrocytes, expands type X collagen and osteopontin expression domains, and reduces chondrocyte proliferation. Retroviral misexpression in chick limb in vivo, histological analysis, molecular marker analysis (type X collagen, osteopontin) Developmental biology High 12482714
2009 Dlx5 is a cell-autonomous regulator of chondrocyte hypertrophy; Col2a1-Dlx5 transgenic mice with Dlx5 restricted specifically to chondrocytes (not perichondrium) display accelerated hypertrophy and mineralization, and this transgene rescues chondrocyte differentiation defects in Dlx5/6 null mice. Chondrocyte-specific transgenic expression (Col2a1-Dlx5), rescue of Dlx5/6 null phenotype, histological analysis PloS one High 19956613
2002 The Dlx5 homeobox gene is essential for vestibular morphogenesis; Dlx5 null mice lack semicircular canals and show shortened endolymphatic duct, and this is accompanied by drastically reduced BMP4 expression in the otic vesicle, placing Bmp4 downstream of Dlx5 in the vestibular development pathway. Dlx5 null mouse analysis, in situ hybridization for Bmp4, Nkx5.1, Pax2, Lfng; immunostaining for sensory markers Developmental biology High 12142028
2010 Loss of either Dlx5 alone or Dlx5&6 together preferentially reduces the number of mature parvalbumin-positive cortical interneurons when mutant immature interneurons are transplanted into wild-type brains, demonstrating a cell-autonomous requirement for Dlx5 in development of parvalbumin-positive interneurons; remaining PV+ interneurons show increased dendritic branching. Cell transplantation of mutant immature interneurons into wild-type brain, conditional Dlx5/6 deletion, electrophysiology, immunohistochemistry for PV/calretinin/somatostatin The Journal of neuroscience : the official journal of the Society for Neuroscience High 20392955
2010 DLX5 directly binds the IRS-2 promoter and transcriptionally activates IRS-2, which in turn sustains AKT phosphorylation; stable knockdown of DLX5 reduces IRS-2 expression, decreases AKT signaling, and inhibits ovarian cancer cell proliferation, while constitutively active AKT rescues this effect. ChIP of DLX5 binding to IRS-2 promoter, shRNA knockdown, constitutively active AKT rescue, luciferase reporter assay, xenograft tumor assay Cancer research High 21045156
2009 DLX5 directly binds two sites in the MYC promoter (shown by EMSA and ChIP) and transcriptionally activates MYC in a dose-dependent manner; knockdown of DLX5 in lung cancer cells reduces MYC expression and proliferation, which is rescued by MYC overexpression. Luciferase promoter assay, EMSA, ChIP, DLX5 overexpression/knockdown, rescue by MYC overexpression The Journal of biological chemistry High 19497851
2009 Loss of Dlx5 in the olfactory epithelium results in olfactory receptor neurons that form normally but fail to generate axons that innervate the olfactory bulb; additionally, Dlx5 has a cell-autonomous effect on neural progenitor ability to produce olfactory bulb local circuit neurons (granule cells more severely affected than periglomerular cells). Dlx5 null mouse analysis, transplantation of Dlx5-/- olfactory bulbs into wild-type neonates, histological and immunochemical characterization The Journal of neuroscience : the official journal of the Society for Neuroscience High 12533617
2008 Dlx5 null osteoblasts show reduced proliferation and differentiation, reduced Runx2/Osx/Osteocalcin/Bone Sialoprotein expression, and a higher RANKL/OPG ratio; Dlx5-/- osteoblasts induce greater osteoclast formation in spleen cultures, establishing that Dlx5-expressing osteoblasts indirectly control osteoclast activity (osteoblast-osteoclast coupling). Dlx5 null mouse embryo femur analysis, osteoblast culture, spleen co-culture osteoclast assay, RANKL/OPG expression measurement The American journal of pathology High 18669617
2009 Calmodulin-dependent kinase II (CaMKII) phosphorylates Dlx5, increases Dlx5 protein stability, and enhances its osteoblastogenic transactivation activity; conversely, the CaMKII inhibitor KN-93 decreases osteogenic and transactivation activities of Dlx5. In vitro kinase assay, co-transfection with CaMKII, reporter assay, CaMKII inhibitor (KN-93) treatment Biochemical and biophysical research communications Medium 19393622
2000 A highly conserved intergenic enhancer (I56i) between Dlx5 and Dlx6 is activated by DLX proteins binding directly to it; Dlx1/2 mutant mice show drastically reduced enhancer activity and reduced Dlx5/6 expression, establishing a cross-regulatory loop where Dlx1/2 drive Dlx5/6 expression through this enhancer. Reporter transgene in transgenic mice and zebrafish, cotransfection assays, DNA-protein binding experiments, analysis in Dlx1/2 double mutant mice The Journal of neuroscience : the official journal of the Society for Neuroscience High 10632600
2014 Dlx5 and Mef2c directly bind a 343-bp osteoblast-specific enhancer ~30 kb upstream of the Runx2 distal promoter; mutation of their binding sites abolishes osteoblast-specific Runx2 enhancer activity in vivo, while other factors (Tcf7, Ctnnb1, Sp7, Smad1, Sox6) are recruited via protein-protein interaction to form an enhanceosome. BAC-GFP reporter mice, serial deletion analysis, ChIP in primary osteoblasts, histone modification analysis, mutagenesis of binding sites in transgenic mice Journal of bone and mineral research High 24692107
2011 Dlx5 directly promotes transcription of Fgf7 in palatal mesenchyme; loss of Dlx5 leads to Fgf7 downregulation and expanded Shh signaling to the nasal side, while exogenous Fgf7 inhibits Shh signaling and reverses CNC cell proliferation rescue in Msx1/Dlx5 double knockout palates. Dlx5 null mice, Msx1/Dlx5 double knockout mice, exogenous Fgf7 treatment of palatal mesenchyme cultures, Shh expression analysis Development (Cambridge, England) Medium 19934017
2011 Hand2 establishes a negative-feedback loop in the distal mandibular arch: Dlx5/6 induce Hand2, and Hand2 subsequently represses Dlx5/6 expression in distal arch ectomesenchyme; failure to repress Dlx5/6 results in upregulation of Runx2, aberrant bone formation, and failure of tongue morphogenesis (aglossia). Hand2 conditional knockout mice, in situ hybridization for Dlx5/6/Hand2/Runx2, histological analysis of mandibular arch Development (Cambridge, England) High 21558373
2014 DLX5 targets the FGF8 locus directly and activates FGF8 expression; FGF8 in turn counteracts Pin1-ΔNp63α interaction, preventing Pin1-mediated proteasomal degradation of p63; p63 SHFM/EEC mutant proteins are resistant to Pin1 action, establishing a DLX5-FGF8-Pin1-p63 regulatory loop in AER stratification. ChIP for DLX5 binding at FGF8 locus, in vitro Pin1-p63 interaction assays, Pin1 null mouse analysis, proteasome inhibitor studies, SHFM/EEC p63 mutant analysis Human molecular genetics Medium 24569166
2011 Chromatin immunoprecipitation confirmed that Dlx5 directly binds the promoters of at least seven genes in the inner ear (Atbf1, Bmper, Large, Lrrtm1, Msx1, Ebf1, and Lhx1), with Bmper and Lrrtm1 upregulated by Dlx5 overexpression, placing Bmp signaling downstream of Dlx5 in the inner ear. Gene expression profiling of WT vs. Dlx5 null otic vesicles, ChIP with Dlx5 antibody in Dlx5-overexpressing cell line, bioinformatic promoter analysis Human molecular genetics Medium 21227998
2004 Neural stem cells from Dlx5-null newborn mice have severely reduced capacity to generate neurons in vitro; forced re-expression of Dlx5 in mutant NSCs fully restores neuronogenic potential, demonstrating a cell-autonomous requirement for Dlx5 in postnatal neurogenesis. Neural stem cell cultures from Dlx5 null mice, forced Dlx5 expression rescue, differentiation assays Molecular and cellular neurosciences Medium 14962748
2010 AMPK activation (via metformin/AICAR) stimulates osteoblast differentiation through a Smad1/5/8-Dlx5-Runx2 signaling cascade; siRNA knockdown of Dlx5 suppresses metformin-induced Runx2 expression, and dominant-negative AMPK blocks Dlx5 induction. AMPK activators/inhibitors, DN-AMPK expression, Dlx5 siRNA knockdown, Runx2-Luc reporter assay, BRE-Luc reporter assay Biochemical and biophysical research communications Medium 21187071
2018 STAT5A negatively regulates Dlx5 expression; STAT5A deletion in mice results in increased trabecular and cortical bone mass, enhanced Dlx5 levels, and increased osteogenesis of BMSCs, with prevention of age-related bone loss. STAT5A conditional knockout mice, siRNA knockdown of STAT5A in hBMSCs, in vivo fracture model, micro-CT bone analysis Cell death & disease Medium 30429452
2018 cAMP/PKA signaling suppresses Dlx5 transcription via sequential activation of CREB and then C/EBPβ; C/EBPβ directly binds a specific site (-517 to -510 bp, site-1) in the Dlx5 promoter to repress its transcription during adipogenic differentiation. cAMP/PKA activators, forced CREB and C/EBPβ expression, siRNA knockdown of C/EBPβ, luciferase promoter assays, ChIP for C/EBPβ at Dlx5 promoter International journal of molecular sciences Medium 30322210
2016 Dlx5 and Dlx6 regulate Msx2 expression cell-autonomously in AER cells and limb mesoderm; in the anterior limb mesoderm, a non-cell-autonomous Msx-Dlx regulatory loop involves BMP molecules through the AER; ChIP analysis confirmed Dlx5/6 regulatory interactions at the Msx2 locus. Triple knockout mice (Msx1/Dlx5/Dlx6 and Msx2/Dlx5/Dlx6), qPCR, ChIP, bioinformatic analysis PloS one Medium 23382810
2017 Dlx5 in CNC cells regulates FGF10 pathway activity; loss of Dlx5 reduces FGF10 signaling and leads to altered proliferation/apoptosis of CNC and muscle progenitor cells in the soft palate; activation of FGF10 signaling rescues CNC cell proliferation and myogenic differentiation in Dlx5 mutant mice. Dlx5 conditional knockout in NCCs (Wnt1-Cre), FGF10 pathway analysis, exogenous FGF10 rescue experiment, lineage tracing Development (Cambridge, England) Medium 28982687
2021 DLX5 cooperates with TP63 to regulate ~2000 enhancers and promoters in squamous cell carcinoma; DLX5 transcriptional activation is directly mediated by SOX2 at the bivalent DLX5 promoter; DLX5 silencing substantially inhibits SCC cell viability in vitro and in vivo. ELMER computational analysis, ChIP-seq for DLX5 and TP63, SOX2 ChIP, shRNA knockdown in vitro and xenograft in vivo, bisulfite sequencing for promoter methylation Nucleic acids research Medium 34370013
2023 DLX5 directly binds the Col10a1 cis-enhancer to promote Col10a1 transcription and chondrocyte hypertrophy; forced DLX5 expression in hypertrophic chondrocytes upregulates RUNX2, suggesting cooperative regulation of Col10a1 by DLX5 and RUNX2 through adjacent binding sites on the enhancer. Dual-luciferase reporter assay, ChIP assay with DLX5 antibody, Dlx5 overexpression and knockdown in MCT and ATDC5 cells, murine OA model Genes & diseases Medium 37492739
1998 An alternative Dlx5 transcript (deltaDlx5) encodes a truncated protein lacking the homeodomain; unlike full-length DLX5, deltaDLX5 is deficient in DNA-binding activity and does not interact with the homeoprotein partner MSX1. RT-PCR cloning, in vitro DNA-binding assay, co-immunoprecipitation/interaction assays The Journal of neuroscience : the official journal of the Society for Neuroscience Medium 9763476
2020 DLX5 and HOXC8 form a protein complex and co-operatively repress LINC01013 lncRNA by directly binding its promoter (ChIP-confirmed); DLX5/HOXC8-mediated repression of LINC01013 enhances chondrogenic differentiation of stem cells from apical papilla. Co-immunoprecipitation for DLX5-HOXC8 complex, ChIP assay for promoter binding, LINC01013 knockdown, pellet culture and in vivo cartilage defect model Stem cell research & therapy Medium 32631410
2011 Allelic reduction of Dlx5 and Dlx6 in mouse ovary results in POI-like phenotype with reduced fertility and early follicular exhaustion; a reciprocal regulation exists between Dlx5/6 and Foxl2 in granulosa cells, and Dlx5/6 reduction leads to upregulation of Foxl2, with both factors having opposing effects on StAR expression. Dlx5/6 hypomorph mice, granulosa cell line transfection, StAR and Foxl2 expression analysis Human molecular genetics Medium 21505076
2015 Dlx5 is expressed by olfactory receptor neurons and controls miR-9 and miR-200 class miRNA levels in the olfactory epithelium; in zebrafish, depletion of miR-9 and miR-200 causes delayed ORN differentiation, altered axonal targeting, and altered GnRH neuron genesis, with miR-9/-200 negatively controlling Foxg1 mRNA. miRNA expression profiling in Dlx5 null olfactory epithelium, miR-9/200 morpholino depletion in zebrafish reporter embryos, foxg1 mRNA overexpression in zebrafish Molecular and cellular neurosciences Medium 25937343
2010 A single nucleotide polymorphism in the ultraconserved Dlx5/6 intergenic enhancer I56i (found in an autistic proband) reduces DLX protein binding affinity in vitro and reduces transcriptional activation of the enhancer by Dlx proteins; affinity purification identified GTF2I as a novel regulator binding the I56i element. Transgenic enhancer reporter mice, in vitro DNA-protein binding affinity assay, affinity purification, electrophoretic mobility shift assay Development (Cambridge, England) Medium 20702565

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome. Nature genetics 440 15608638
1999 Craniofacial, vestibular and bone defects in mice lacking the Distal-less-related gene Dlx5. Development (Cambridge, England) 359 10433909
2003 BMP-2-induced Runx2 expression is mediated by Dlx5, and TGF-beta 1 opposes the BMP-2-induced osteoblast differentiation by suppression of Dlx5 expression. The Journal of biological chemistry 350 12815054
2002 The Dlx5 and Dlx6 homeobox genes are essential for craniofacial, axial, and appendicular skeletal development. Genes & development 340 12000792
2003 BMP-2-induced Osterix expression is mediated by Dlx5 but is independent of Runx2. Biochemical and biophysical research communications 331 12963046
1999 Dlx5 regulates regional development of the branchial arches and sensory capsules. Development (Cambridge, England) 288 10433912
2000 A highly conserved enhancer in the Dlx5/Dlx6 intergenic region is the site of cross-regulatory interactions between Dlx genes in the embryonic forebrain. The Journal of neuroscience : the official journal of the Society for Neuroscience 275 10632600
1999 DLX-1, DLX-2, and DLX-5 expression define distinct stages of basal forebrain differentiation. The Journal of comparative neurology 237 10516593
2004 Dlx3 transcriptional regulation of osteoblast differentiation: temporal recruitment of Msx2, Dlx3, and Dlx5 homeodomain proteins to chromatin of the osteocalcin gene. Molecular and cellular biology 230 15456894
2007 BMP-2 induces Osterix expression through up-regulation of Dlx5 and its phosphorylation by p38. The Journal of biological chemistry 185 18056716
2005 Dlx5 specifically regulates Runx2 type II expression by binding to homeodomain-response elements in the Runx2 distal promoter. The Journal of biological chemistry 171 16115867
2004 Bone morphogenetic protein-2-induced alkaline phosphatase expression is stimulated by Dlx5 and repressed by Msx2. The Journal of biological chemistry 163 15383550
1999 A BMP-inducible gene, dlx5, regulates osteoblast differentiation and mesoderm induction. Developmental biology 161 10075846
2002 Jaw transformation with gain of symmetry after Dlx5/Dlx6 inactivation: mirror of the past? Genesis (New York, N.Y. : 2000) 157 12434331
2001 Regulation of the activity of the transcription factor Runx2 by two homeobox proteins, Msx2 and Dlx5. Genes to cells : devoted to molecular & cellular mechanisms 148 11683913
2004 Segregation of lens and olfactory precursors from a common territory: cell sorting and reciprocity of Dlx5 and Pax6 expression. Developmental biology 140 15223343
2010 Dlx5 and Dlx6 regulate the development of parvalbumin-expressing cortical interneurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 139 20392955
2003 DLX5 positions the neural crest and preplacode region at the border of the neural plate. Developmental biology 122 12812786
1998 Reciprocal regulation of osteocalcin transcription by the homeodomain proteins Msx2 and Dlx5. Biochemistry 120 9819228
2003 DLX5 regulates development of peripheral and central components of the olfactory system. The Journal of neuroscience : the official journal of the Society for Neuroscience 110 12533617
2014 Dlx5 and mef2 regulate a novel runx2 enhancer for osteoblast-specific expression. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 102 24692107
2010 Tumor necrosis factor-α accelerates the calcification of human aortic valve interstitial cells obtained from patients with calcific aortic valve stenosis via the BMP2-Dlx5 pathway. The Journal of pharmacology and experimental therapeutics 100 21205918
2002 A RING finger protein Praja1 regulates Dlx5-dependent transcription through its ubiquitin ligase activity for the Dlx/Msx-interacting MAGE/Necdin family protein, Dlxin-1. The Journal of biological chemistry 93 11959851
2000 Dlxin-1, a novel protein that binds Dlx5 and regulates its transcriptional function. The Journal of biological chemistry 92 11084035
1995 The expression pattern of the Distal-less homeobox-containing gene Dlx-5 in the developing chick limb bud suggests its involvement in apical ectodermal ridge activity, pattern formation, and cartilage differentiation. Mechanisms of development 92 8541214
1998 An early phase of embryonic Dlx5 expression defines the rostral boundary of the neural plate. The Journal of neuroscience : the official journal of the Society for Neuroscience 90 9763476
2008 Dlx5, a positive regulator of osteoblastogenesis, is essential for osteoblast-osteoclast coupling. The American journal of pathology 89 18669617
2007 Dlx5 drives Runx2 expression and osteogenic differentiation in developing cranial suture mesenchyme. Developmental biology 89 17335796
2002 The Dlx5 homeobox gene is essential for vestibular morphogenesis in the mouse embryo through a BMP4-mediated pathway. Developmental biology 87 12142028
2010 AMP-activated protein kinase (AMPK) positively regulates osteoblast differentiation via induction of Dlx5-dependent Runx2 expression in MC3T3E1 cells. Biochemical and biophysical research communications 78 21187071
2003 BMP signals regulate Dlx5 during early avian skull development. Developmental biology 74 12710966
2011 Downregulation of Dlx5 and Dlx6 expression by Hand2 is essential for initiation of tongue morphogenesis. Development (Cambridge, England) 73 21558373
2011 Identification of a novel DLX5 mutation in a family with autosomal recessive split hand and foot malformation. Journal of medical genetics 71 22121204
2009 Indirect modulation of Shh signaling by Dlx5 affects the oral-nasal patterning of palate and rescues cleft palate in Msx1-null mice. Development (Cambridge, England) 66 19934017
2002 Overexpression of Dlx5 in chicken calvarial cells accelerates osteoblastic differentiation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 66 12054155
2002 Dlx5 is a positive regulator of chondrocyte differentiation during endochondral ossification. Developmental biology 64 12482714
2001 Distinct roles for Distal-less genes Dlx3 and Dlx5 in regulating ectodermal development in Xenopus. Molecular reproduction and development 62 11599044
2003 The Dlx5 homeodomain gene is essential for olfactory development and connectivity in the mouse. Molecular and cellular neurosciences 61 12727448
2010 An SNP in an ultraconserved regulatory element affects Dlx5/Dlx6 regulation in the forebrain. Development (Cambridge, England) 59 20702565
2017 Disturbed Placental Imprinting in Preeclampsia Leads to Altered Expression of DLX5, a Human-Specific Early Trophoblast Marker. Circulation 58 28904069
2005 Msx1 and Dlx5 act independently in development of craniofacial skeleton, but converge on the regulation of Bmp signaling in palate formation. Mechanisms of development 57 16330189
2015 Different Methylation Patterns of RUNX2, OSX, DLX5 and BSP in Osteoblastic Differentiation of Mesenchymal Stem Cells. Cell journal 55 25870836
2010 Upregulation of DLX5 promotes ovarian cancer cell proliferation by enhancing IRS-2-AKT signaling. Cancer research 52 21045156
2012 Functional characterization of tissue-specific enhancers in the DLX5/6 locus. Human molecular genetics 51 22914741
2015 The Dlx5 and Foxg1 transcription factors, linked via miRNA-9 and -200, are required for the development of the olfactory and GnRH system. Molecular and cellular neurosciences 50 25937343
2008 TGF-beta mediated Dlx5 signaling plays a crucial role in osteo-chondroprogenitor cell lineage determination during mandible development. Developmental biology 50 18684439
2004 Defective neuronogenesis in the absence of Dlx5. Molecular and cellular neurosciences 49 14962748
2006 Dlx5 and Dlx6 homeobox genes are required for specification of the mammalian vestibular apparatus. Genesis (New York, N.Y. : 2000) 45 16900517
2007 DLX5 and DLX6 expression is biallelic and not modulated by MeCP2 deficiency. American journal of human genetics 44 17701895
2003 Msx1/Bmp4 genetic pathway regulates mammalian alveolar bone formation via induction of Dlx5 and Cbfa1. Mechanisms of development 41 14654219
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
2003 Dlx5 regulates chondrocyte differentiation at multiple stages. The International journal of developmental biology 40 12895028
2009 DLX5 (distal-less homeobox 5) promotes tumor cell proliferation by transcriptionally regulating MYC. The Journal of biological chemistry 39 19497851
2019 Dlx5 and Dlx6 expression in GABAergic neurons controls behavior, metabolism, healthy aging and lifespan. Aging 37 31514171
2010 Deletion of an enhancer near DLX5 and DLX6 in a family with hearing loss, craniofacial defects, and an inv(7)(q21.3q35). Human genetics 37 19707792
2020 DLX5 and HOXC8 enhance the chondrogenic differentiation potential of stem cells from apical papilla via LINC01013. Stem cell research & therapy 36 32631410
2016 miR-203 and miR-320 Regulate Bone Morphogenetic Protein-2-Induced Osteoblast Differentiation by Targeting Distal-Less Homeobox 5 (Dlx5). Genes 35 28025541
2014 Next generation sequencing of chromosomal rearrangements in patients with split-hand/split-foot malformation provides evidence for DYNC1I1 exonic enhancers of DLX5/6 expression in humans. Journal of medical genetics 35 24459211
2014 DLX5, FGF8 and the Pin1 isomerase control ΔNp63α protein stability during limb development: a regulatory loop at the basis of the SHFM and EEC congenital malformations. Human molecular genetics 34 24569166
2014 MiR-124 inhibits myogenic differentiation of mesenchymal stem cells via targeting Dlx5. Journal of cellular biochemistry 32 24733577
2004 Dlx5, the mouse homologue of the human-imprinted DLX5 gene, is biallelically expressed in the mouse brain. Journal of human genetics 31 15362572
2002 An L1 element disrupts human bone sialoprotein promoter: lack of tissue-specific regulation by distalless5 (Dlx5) and runt homeodomain protein2 (Runx2)/core binding factor a1 (Cbfa1) elements. Gene 31 12459268
2016 Exclusion of Dlx5/6 expression from the distal-most mandibular arches enables BMP-mediated specification of the distal cap. Proceedings of the National Academy of Sciences of the United States of America 30 27335460
2014 Exome sequencing reveals a heterozygous DLX5 mutation in a Chinese family with autosomal-dominant split-hand/foot malformation. European journal of human genetics : EJHG 30 24496061
2008 A novel recurrent chromosomal inversion implicates the homeobox gene Dlx5 in T-cell lymphomas from Lck-Akt2 transgenic mice. Cancer research 30 18316591
2020 LacZ-reporter mapping of Dlx5/6 expression and genoarchitectural analysis of the postnatal mouse prethalamus. The Journal of comparative neurology 29 32420617
2010 Msx1 and Dlx5 function synergistically to regulate frontal bone development. Genesis (New York, N.Y. : 2000) 29 20824629
2017 The Dlx5-FGF10 signaling cascade controls cranial neural crest and myoblast interaction during oropharyngeal patterning and development. Development (Cambridge, England) 28 28982687
2015 Dlx5 and Dlx6 control uterine adenogenesis during post-natal maturation: possible consequences for endometriosis. Human molecular genetics 28 26512061
2013 BMP-mediated functional cooperation between Dlx5;Dlx6 and Msx1;Msx2 during mammalian limb development. PloS one 28 23382810
2018 Inhibition of STAT5A promotes osteogenesis by DLX5 regulation. Cell death & disease 26 30429452
2011 Identification of direct downstream targets of Dlx5 during early inner ear development. Human molecular genetics 26 21227998
2003 Dlx5/6-enhancer directed expression of Cre recombinase in the pharyngeal arches and brain. Genesis (New York, N.Y. : 2000) 26 14666512
2010 Polymethylmethacrylate particles impair osteoprogenitor viability and expression of osteogenic transcription factors Runx2, osterix, and Dlx5. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 25 20014320
1999 Dlx-5 in limb initiation in the chick embryo. Developmental dynamics : an official publication of the American Association of Anatomists 25 10474161
2009 Expression analysis and mutation detection of DLX5 and DLX6 in autism. Brain & development 24 19195802
2021 Activation of bivalent factor DLX5 cooperates with master regulator TP63 to promote squamous cell carcinoma. Nucleic acids research 23 34370013
2008 Isolation and imprinting analysis of the porcine DLX5 gene and its association with carcass traits. Animal genetics 23 18498429
2006 Dlx5- and Dlx6-mediated chondrogenesis: Differential domain requirements for a conserved function. Mechanisms of development 23 17027239
2023 DLX5 promotes Col10a1 expression and chondrocyte hypertrophy and is involved in osteoarthritis progression. Genes & diseases 22 37492739
2020 RETRACTED: KDM4A promotes the growth of non-small cell lung cancer by mediating the expression of Myc via DLX5 through the Wnt/β-catenin signaling pathway. Life sciences 22 33002480
2014 Absent expression of the osteoblast-specific maternally imprinted genes, DLX5 and DLX6, causes split hand/split foot malformation type I. Journal of medical genetics 22 25332435
2016 Transcriptome analysis of periodontitis-associated fibroblasts by CAGE sequencing identified DLX5 and RUNX2 long variant as novel regulators involved in periodontitis. Scientific reports 21 27645561
2018 T-614 Promotes Osteoblastic Cell Differentiation by Increasing Dlx5 Expression and Regulating the Activation of p38 and NF-κB. BioMed research international 20 29670900
2014 BRONJ-related jaw bone is associated with increased Dlx-5 and suppressed osteopontin-implication in the site-specific alteration of angiogenesis and bone turnover by bisphosphonates. Clinical oral investigations 20 25467232
2009 Dlx5 Is a cell autonomous regulator of chondrocyte hypertrophy in mice and functionally substitutes for Dlx6 during endochondral ossification. PloS one 20 19956613
2009 Calmodulin-dependent kinase II regulates Dlx5 during osteoblast differentiation. Biochemical and biophysical research communications 19 19393622
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
2019 Down-regulation of miR-339 promotes differentiation of BMSCs and alleviates osteoporosis by targeting DLX5. European review for medical and pharmacological sciences 18 30657543
2018 miR‑339‑5p negatively regulates loureirin A‑induced hair follicle stem cell differentiation by targeting DLX5. Molecular medicine reports 18 29901112
2014 Expression of GAD67 and Dlx5 in the taste buds of mice genetically lacking Mash1. Chemical senses 18 24682237
2014 Heterozygous DLX5 nonsense mutation associated with isolated split-hand/foot malformation with reduced penetrance and variable expressivity in two unrelated families. Birth defects research. Part A, Clinical and molecular teratology 18 25196357
1999 Expression of DLX5 during human embryonic craniofacial development. Mechanisms of development 18 10330497
2018 Deletion of a Long-Range Dlx5 Enhancer Disrupts Inner Ear Development in Mice. Genetics 17 29301908
2018 Probing the origin of matching functional jaws: roles of Dlx5/6 in cranial neural crest cells. Scientific reports 17 30297736
2018 cAMP/Protein Kinase A Signaling Inhibits Dlx5 Expression via Activation of CREB and Subsequent C/EBPβ Induction in 3T3-L1 Preadipocytes. International journal of molecular sciences 17 30322210
2013 Endothelin regulates neural crest deployment and fate to form great vessels through Dlx5/Dlx6-independent mechanisms. Mechanisms of development 17 23933587
2012 Rapp-Hodgkin syndrome and SHFM1 patients: delineating the p63-Dlx5/Dlx6 pathway. Gene 17 22342398
2011 Allelic reduction of Dlx5 and Dlx6 results in early follicular depletion: a new mouse model of primary ovarian insufficiency. Human molecular genetics 17 21505076
2017 Increased methylation and decreased expression of homeobox genes TLX1, HOXA10 and DLX5 in human placenta are associated with trophoblast differentiation. Scientific reports 16 28674422

Missed literature

Know a paper Affinage missed for DLX5? Flag it for the maintainers and the community.

No submissions yet.