Affinage

DLX5

Homeobox protein DLX-5 · UniProt P56178

Length
289 aa
Mass
31.5 kDa
Annotated
2026-04-28
100 papers in source corpus 43 papers cited in narrative 42 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DLX5 is a homeodomain transcription factor that functions as a central integrator of skeletal patterning, osteoblast/chondrocyte differentiation, craniofacial morphogenesis, inner ear development, and GABAergic interneuron specification. In the osteogenic lineage, DLX5 acts as a BMP-2/4-inducible immediate-early gene that directly binds homeodomain-response elements in the promoters and enhancers of Runx2, Osterix, alkaline phosphatase, osteocalcin, and Col10a1 to drive differentiation; its transactivation is enhanced by p38 MAPK phosphorylation at Ser-34/Ser-217 and by CaMKII-mediated stabilization, while DLX5 antagonizes MSX2-mediated transcriptional repression through direct homeodomain–homeodomain interaction and competition for shared cis-elements (PMID:10075846, PMID:9819228, PMID:16115867, PMID:18056716, PMID:15383550). Compound Dlx5/Dlx6 loss causes homeotic jaw transformation, split-hand/foot malformation, absent semicircular canals, and loss of parvalbumin-positive cortical interneurons with spontaneous seizures, establishing essential non-redundant roles in mandibular identity, limb outgrowth, vestibular morphogenesis, and forebrain GABAergic circuit assembly (PMID:12434331, PMID:12000792, PMID:12142028, PMID:20392955). In cancer contexts, DLX5 directly activates MYC, IRS-2, and NOTCH1 transcription to promote proliferation via AKT and Notch signaling axes (PMID:19497851, PMID:21045156, PMID:34249467).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1998 High

    Establishing that DLX5 physically interacts with MSX2 through homeodomain regions and antagonizes MSX2-mediated transcriptional repression resolved how two competing homeodomain factors calibrate osteocalcin gene expression.

    Evidence Far-Western blot, EMSA, structure-function deletion analysis, and luciferase reporter assay in osteoblastic cells

    PMID:9819228

    Open questions at the time
    • Whether DLX5–MSX2 antagonism operates genome-wide or only at select promoters
    • No structural model of the DLX5–MSX2 dimer
  2. 1999 High

    Dlx5 knockout mice revealed that this gene is required for craniofacial patterning, vestibular organ morphogenesis, and osteoblast differentiation in vivo, establishing its non-redundant developmental roles.

    Evidence Targeted gene knockout replacing exons I and II with lacZ; phenotypic analysis of homozygous mutant mice in two independent studies

    PMID:10433909 PMID:10433912

    Open questions at the time
    • Functional redundancy with Dlx6 not resolved by single knockout
    • Downstream transcriptional targets not yet identified
  3. 1999 High

    Demonstrating that Dlx5 is a direct BMP-2/4-inducible gene that promotes osteoblast differentiation upon overexpression positioned it as a key effector downstream of BMP signaling in the osteogenic cascade.

    Evidence BMP-inducible gene isolation and stable overexpression in MC3T3-E1 cells with ALP, osteocalcin, and mineralization readouts

    PMID:10075846

    Open questions at the time
    • Whether Dlx5 is sufficient or merely necessary for BMP-induced osteogenesis
    • Direct promoter targets of DLX5 not yet mapped
  4. 2000 High

    Identification of a conserved Dlx5/Dlx6 intergenic enhancer bound and activated by DLX1/2 proteins established the cross-regulatory cascade by which Dlx1/2 control Dlx5/6 forebrain expression.

    Evidence Transgenic reporter mice and zebrafish; Dlx1/2 double mutant analysis; EMSA and cotransfection reporter assays

    PMID:10632600

    Open questions at the time
    • Identity of all trans-acting factors at this enhancer
    • Whether this cascade operates in non-forebrain tissues
  5. 2002 High

    Discovery that Dlxin-1 directly binds and coactivates DLX5, and that the E3 ligase Praja1 controls Dlxin-1 levels via ubiquitin-proteasome degradation, revealed a protein-level regulatory circuit tuning DLX5 transcriptional output.

    Evidence Yeast two-hybrid, GST pulldown, Co-IP, in vivo ubiquitination assay, RING mutant, proteasome inhibitor rescue, GAL4 reporter

    PMID:11084035 PMID:11959851

    Open questions at the time
    • Physiological tissues and conditions where Praja1-Dlxin-1 axis regulates DLX5 in vivo
    • Whether other DLX family members are similarly regulated
  6. 2002 High

    Dlx5/Dlx6 double knockouts showed homeotic jaw transformation, split-hand/foot malformation rescued by AER-specific Dlx5, and vestibular defects, demonstrating that the two genes together specify mandibular identity, limb outgrowth, and inner ear patterning.

    Evidence Double knockout mice; tissue-specific transgenic rescue; in situ hybridization for downstream targets (BMP4, Pax2, Gbx2)

    PMID:12000792 PMID:12142028 PMID:12434331

    Open questions at the time
    • Degree of functional equivalence between Dlx5 and Dlx6
    • Direct enhancer targets mediating limb outgrowth not mapped
  7. 2003 High

    Epistasis experiments showed DLX5 is indispensable for BMP-2-induced expression of both Runx2 and Osterix, with Osterix induction independent of Runx2, establishing DLX5 as a branching node in the osteogenic transcription factor hierarchy.

    Evidence Antisense knockdown of Dlx5; BMP-2 treatment in Runx2-null cells; cycloheximide treatment in C2C12 cells

    PMID:12815054 PMID:12963046

    Open questions at the time
    • Whether DLX5 binds Osterix and Runx2 promoters directly (resolved later)
    • In vivo validation of linear pathway
  8. 2004 High

    Direct DNA binding of DLX5 to the alkaline phosphatase promoter and temporal ChIP analysis of osteocalcin chromatin occupancy demonstrated that DLX5 functions as a direct transcriptional activator that replaces MSX2 at target promoters during osteoblast maturation.

    Evidence EMSA, site-directed mutagenesis, ChIP time-course in differentiating osteoblasts, Runx2-null cell experiments

    PMID:15383550 PMID:15456894

    Open questions at the time
    • Global set of direct DLX5 target promoters not yet defined
    • Mechanism of MSX2-to-DLX5 switch unclear
  9. 2004 High

    MeCP2-mediated formation of a silent chromatin loop at the Dlx5/Dlx6 locus in mouse brain, lost upon MeCP2 deletion, linked Rett syndrome pathology to DLX5 de-repression and provided a paradigm for epigenetic regulation of homeodomain gene clusters.

    Evidence ChIP, chromatin loop assay (ChIP-loop), Mecp2-null mouse brains, allele-specific expression analysis

    PMID:15608638

    Open questions at the time
    • Whether Dlx5 de-repression causally contributes to Rett syndrome phenotypes
    • Whether the loop is cell-type specific within brain
  10. 2005 High

    Mapping of three homeodomain-response elements in the Runx2-P1 promoter directly bound and transactivated by DLX5 (and antagonized by MSX2) confirmed DLX5 as a direct upstream activator of Runx2 transcription.

    Evidence EMSA, site-directed mutagenesis of individual elements, promoter-reporter assay in C2C12 cells

    PMID:16115867

    Open questions at the time
    • In vivo ChIP validation at endogenous Runx2 locus not yet performed
  11. 2007 High

    Demonstrating that p38 MAPK phosphorylates DLX5 at Ser-34 and Ser-217 to enhance its transactivation of the Osterix promoter revealed a key post-translational mechanism integrating MAPK signaling with the osteogenic transcription factor cascade.

    Evidence In vitro kinase assay, phosphosite mutagenesis, ChIP at Osterix promoter, BMP-2-stimulated osteoblasts

    PMID:18056716

    Open questions at the time
    • Whether other kinases target these same sites in vivo
    • Crystal structure of phospho-DLX5 not available
  12. 2008 High

    Dlx5-null osteoblast analysis showed that DLX5 regulates the RANKL/OPG ratio, linking it to osteoblast-osteoclast coupling, while TGF-β receptor conditional knockouts demonstrated that TGF-β suppresses Dlx5 to maintain chondrogenic potential over osteogenic fate.

    Evidence Dlx5 null mouse femur analysis; co-culture osteoclastogenesis assay; compound Tgfbr2/Dlx5 conditional knockout rescue

    PMID:18669617 PMID:18684439

    Open questions at the time
    • Whether DLX5 directly controls RANKL or OPG promoters
    • Full epistatic relationship between TGF-β and BMP at the Dlx5 promoter
  13. 2009 High

    Identification of MYC and IRS-2 as direct DLX5 transcriptional targets (confirmed by EMSA and ChIP) established pro-proliferative functions for DLX5 in cancer via MYC activation and IRS-2/AKT signaling, extending its role beyond developmental contexts.

    Evidence EMSA, ChIP, luciferase reporters, siRNA/shRNA knockdown with rescue by MYC or constitutively active AKT; xenograft tumor assays

    PMID:19497851 PMID:21045156

    Open questions at the time
    • Whether DLX5 oncogenic functions depend on the same phosphorylation events as osteogenic functions
    • Prevalence of DLX5 activation across cancer types
  14. 2009 Medium

    CaMKII phosphorylation of DLX5 increases its protein stability and osteoblastogenic transactivation, adding a second kinase pathway that post-translationally amplifies DLX5 activity.

    Evidence In vitro kinase assay; protein stability assay; transcriptional reporter; KN-93 pharmacological inhibition

    PMID:19393622

    Open questions at the time
    • Specific CaMKII phosphorylation sites on DLX5 not mapped
    • In vivo confirmation of CaMKII-DLX5 axis not provided
  15. 2010 High

    Dlx5/Dlx6 were shown to be required for parvalbumin-positive cortical interneuron development and tangential migration; heterozygous loss caused spontaneous seizures and impaired gamma oscillations, linking Dlx5/6 dosage to circuit-level function.

    Evidence Conditional knockout; interneuron transplantation assay; EEG recording; immunohistochemistry; CXCR4 expression analysis

    PMID:20392955

    Open questions at the time
    • Direct transcriptional targets of DLX5 in interneurons not identified
    • Whether seizure phenotype is specifically due to parvalbumin+ neuron loss
  16. 2010 High

    Hand2 was identified as a negative-feedback regulator of Dlx5/6 in distal mandibular arch mesenchyme; failure to repress Dlx5/6 causes ectopic bone and aglossia, resolving how Dlx5/6 expression is spatially refined.

    Evidence Conditional knockout of Hand2; compound Hand2/Dlx5/6 mutants; in situ hybridization

    PMID:21558373

    Open questions at the time
    • Whether Hand2 directly binds Dlx5/6 regulatory regions
    • Mechanism of Dlx5/6 repression by Hand2 unknown
  17. 2014 High

    In vivo ChIP and enhancer mutagenesis in transgenic mice demonstrated that DLX5 and MEF2 directly bind a conserved enhancer 30 kb upstream of Runx2, required for osteoblast-specific Runx2 expression, defining the cis-regulatory architecture of this key osteogenic locus.

    Evidence BAC reporter mouse; serial deletion and in vivo mutagenesis of binding sites; ChIP in primary osteoblasts; histone modification analysis

    PMID:24692107

    Open questions at the time
    • Three-dimensional chromatin topology at the Runx2 locus not characterized
    • Whether this enhancer operates in chondrocytes
  18. 2019 Medium

    GABAergic-specific Dlx5/6 inactivation reduced anxiety, obsessive-compulsive behaviors, adiposity, and extended lifespan by 33%, revealing unexpected metabolic and longevity roles for Dlx5/6 in mature GABAergic circuits.

    Evidence Conditional knockout (Vgat-Cre; Dlx5/6 flox); behavioral testing; body composition and survival analysis

    PMID:31514171

    Open questions at the time
    • Downstream metabolic effectors in GABAergic neurons not identified
    • Whether longevity effect is due to reduced adiposity or altered behavior
    • Independent replication needed
  19. 2021 Medium

    Genome-wide chromatin profiling revealed that DLX5 cooperates with TP63 at ~2000 enhancers in squamous cell carcinoma, with DLX5 reactivation driven by SOX2-mediated switching of its promoter from bivalent to active chromatin state.

    Evidence ATAC-seq, ChIP-seq, ELMER analysis, shRNA knockdown, xenograft assay in ESCC

    PMID:34370013

    Open questions at the time
    • Direct physical interaction between DLX5 and TP63 not confirmed
    • Mechanism by which DLX5 selects enhancers genome-wide unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include the complete set of direct DLX5 transcriptional targets in GABAergic interneurons, the structural basis for homeodomain-mediated partner interactions, and whether post-translational modifications that enhance osteogenic DLX5 activity also operate in neural or oncogenic contexts.
  • No genome-wide direct target map (CUT&RUN/ChIP-seq) in interneurons
  • No crystal or cryo-EM structure of DLX5 homeodomain in complex with DNA or protein partners
  • Phosphorylation-site mapping in neural tissues not performed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 10 GO:0003677 DNA binding 8
Localization
GO:0005634 nucleus 6
Pathway
R-HSA-74160 Gene expression (Transcription) 9 R-HSA-1266738 Developmental Biology 8 R-HSA-162582 Signal Transduction 5
Partners
DLX6DLXIN1MEF2MSX2PRAJA1RUNX2TP63

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Dlx5 null mice exhibit craniofacial abnormalities, vestibular malformations, and defective osteogenesis, establishing that Dlx5 is required for patterning of branchial arch derivatives, morphogenesis of the vestibular organ, and osteoblast differentiation in vivo. Targeted gene knockout (null allele replacing exons I and II with lacZ); phenotypic analysis of homozygous mutants Development (Cambridge, England) High 10433909 10433912
1999 Dlx5 is a direct transcriptional target of BMP signaling (BMP-2 and BMP-4) in osteoblastic cells; overexpression of Dlx5 in MC3T3-E1 cells increases alkaline phosphatase activity, osteocalcin production, and mineralization, demonstrating a functional role in osteoblast differentiation downstream of BMP. BMP-inducible gene isolation; stable transfection overexpression assay; osteogenic marker measurement Developmental biology High 10075846
1998 DLX5 and MSX2 form dimers via their homeodomain regions; DLX5 (residues 127–143) de-represses Msx2-mediated transcriptional repression of the osteocalcin promoter by antagonizing Msx2 binding and restoring OCFREB binding activity, without requiring its own intrinsic DNA-binding activity. Far-Western blot (protein-protein interaction); transient cotransfection/luciferase reporter assay; structure-function deletion analysis; EMSA Biochemistry High 9819228
2003 DLX5 is an indispensable mediator of BMP-2-induced Runx2 expression in C2C12 cells; DLX5 is immediately induced by BMP-2 (cycloheximide-resistant), whereas Runx2 induction requires de novo protein synthesis. Antisense blocking of Dlx5 abolishes BMP-2-induced Runx2 expression. TGF-β1 opposes BMP-2-induced osteogenesis by suppressing Dlx5 expression through de novo AP-1 induction. Cycloheximide treatment; antisense knockdown; overexpression in C2C12 cells; osteogenic marker assays The Journal of biological chemistry High 12815054
2003 BMP-2-induced Osterix expression requires Dlx5 but not Runx2: Osx is still induced by BMP-2 in Runx2-null cells, but antisense blocking of Dlx5 completely abrogates BMP-2-induced Osx expression. Antisense Dlx5 knockdown; BMP-2 treatment in Runx2-null cells; gene expression analysis Biochemical and biophysical research communications High 12963046
2001 DLX5 interferes with MSX2-Runx2 protein-protein interaction and relieves MSX2-mediated repression of Runx2 transcriptional activity; a missense mutation of MSX2 (P148H) associated with craniosynostosis retains ability to bind and repress Runx2, but is insensitive to DLX5 counter-regulation. Co-immunoprecipitation; transcriptional reporter assays; domain mapping Genes to cells : devoted to molecular & cellular mechanisms High 11683913
2004 DLX5 directly binds a cis-acting element in the alkaline phosphatase promoter (identified by EMSA and site-directed mutagenesis) and transactivates ALP expression; MSX2 competes with DLX5 for this same element to suppress ALP expression; DLX5-stimulated ALP activity is independent of Runx2. EMSA; site-directed mutagenesis; promoter-reporter assay; Runx2-null cell experiments The Journal of biological chemistry High 15383550
2005 DLX5 specifically transactivates the Runx2 type II (P1 distal) promoter by binding to three homeodomain-response elements between −756 and −342 bp; this activity is confirmed by gel mobility shift assay and site-directed mutagenesis and is antagonized by MSX2 at the same region. Promoter deletion analysis; gel mobility shift assay (EMSA); site-directed mutagenesis; reporter assay; overexpression in C2C12 cells The Journal of biological chemistry High 16115867
2002 Dlxin-1 (MAGE/Necdin family protein) directly binds DLX5 (and DLX7 and MSX2) and activates DLX5-dependent transcription; interaction confirmed by yeast two-hybrid, GST pulldown, and co-immunoprecipitation. Yeast two-hybrid screening; GST pulldown; co-immunoprecipitation; reporter gene assay The Journal of biological chemistry High 11084035
2002 The RING finger E3 ubiquitin ligase Praja1 binds the C-terminal necdin homology domain of Dlxin-1 and promotes its ubiquitin-dependent proteasomal degradation, thereby down-regulating DLX5-dependent transcriptional activity. Yeast two-hybrid; GST pulldown; co-immunoprecipitation; proteasome inhibitor rescue; in vivo ubiquitination assay; RING mutant; GAL4 reporter assay The Journal of biological chemistry High 11959851
2007 DLX5 binds to homeodomain-response elements in the Osterix promoter (confirmed by EMSA and ChIP), and is phosphorylated by p38 MAPK at Ser-34 and Ser-217 in vitro and in vivo; this phosphorylation increases DLX5 transactivation potential and is required for full BMP-2-induced Osterix induction. EMSA; ChIP; in vitro kinase assay; site-directed mutagenesis (Ser-34/217); overexpression and knockdown The Journal of biological chemistry High 18056716
2004 MeCP2 recruits histone deacetylase 1 (HDAC1) to the Dlx5-Dlx6 locus in mouse brain, promotes repressive H3K9 methylation at this ~1-kb region, and mediates formation of an 11-kb silent chromatin loop at the locus; loss of MeCP2 (in Mecp2-null mice) abolishes this loop and de-represses Dlx5-Dlx6 expression approximately two-fold. ChIP; chromatin loop assay (ChIP-loop); Mecp2-null mouse brains; allele-specific expression analysis Nature genetics High 15608638
2002 Combined inactivation of Dlx5 and Dlx6 in mice causes homeotic-like transformation of the lower jaw into an upper jaw (gain of symmetry), demonstrating that Dlx5/Dlx6 together specify mandibular/lower jaw identity in the first pharyngeal arch. Double knockout mice; skeletal phenotype analysis Genesis (New York, N.Y. : 2000) High 12434331
2002 Combined deletion of Dlx5 and Dlx6 in mice causes severe craniofacial, axial, and appendicular skeletal defects phenocopying split-hand/foot malformation (SHFM); transgenic overexpression of Dlx5 specifically in the apical ectodermal ridge fully rescues limb outgrowth in Dlx5/6 null mice, demonstrating that AER-expressed Dlx5 is sufficient for this function. Double knockout mice; tissue-specific transgenic rescue experiment Genes & development High 12000792
2002 The Dlx5 homeobox gene is essential for vestibular morphogenesis through regulation of BMP4 expression: Dlx5 null mice lack semicircular canals and have severely reduced BMP4 expression in the otic vesicle, while Nkx5.1, Pax2, and Lfng expression is unchanged. Dlx5 null mouse analysis; in situ hybridization for downstream genes; comparative marker analysis Developmental biology High 12142028
2004 During osteoblast differentiation, a temporal molecular switch occurs at the osteocalcin gene promoter: Msx2 occupies it in proliferating osteoblasts (repressing transcription), while Dlx3, Dlx5, and Runx2 are recruited post-proliferatively to activate transcription; Dlx5 occupancy increases over Dlx3 at the mineralization stage. Dlx3 and Runx2 directly interact (mapped to Runx2 residues 376–432). Chromatin immunoprecipitation (ChIP); co-immunoprecipitation; reporter assay; RNA interference knockdown Molecular and cellular biology High 15456894
2009 DLX5 directly binds the IRS-2 promoter (confirmed by ChIP and luciferase assay) and augments its transcription; DLX5-driven cell proliferation in ovarian cancer cells operates through the IRS-2-AKT signaling axis, as knockdown of IRS-2 and MET suppresses AKT phosphorylation downstream of DLX5. ChIP; luciferase reporter assay; shRNA stable knockdown; constitutively active AKT rescue; xenograft tumor growth assay Cancer research High 21045156
2009 DLX5 directly binds two sites in the MYC promoter (confirmed by EMSA and ChIP) and specifically activates MYC transcription in a dose-dependent manner; DLX5-mediated cell proliferation is rescued by MYC overexpression following DLX5 knockdown, placing MYC downstream of DLX5. Luciferase reporter assay; EMSA; ChIP; siRNA knockdown; MYC overexpression rescue The Journal of biological chemistry High 19497851
2009 DLX5 is a cell-autonomous regulator of chondrocyte hypertrophy during endochondral ossification: Col2a1-Dlx5 transgenic mice with chondrocyte-restricted Dlx5 expression show accelerated chondrocyte hypertrophy and mineralization, and this transgene specifically rescues the chondrocyte differentiation defects of Dlx5/6 null mice. Dlx5 and Dlx6 are functionally equivalent in this context. Chondrocyte-specific transgenic expression (Col2a1 promoter); rescue of Dlx5/6 null phenotype PloS one High 19956613
2008 Dlx5 null osteoblasts show reduced expression of Runx2, Osterix, Osteocalcin, and Bone Sialoprotein; Dlx5(-/-) femurs have increased osteoclast numbers and Dlx5(-/-) osteoblasts show a higher RANKL/OPG ratio, inducing more TRAP-positive multinucleated osteoclast-like cells in co-culture. This establishes Dlx5 as a regulator of osteoblast-osteoclast coupling. Dlx5 null mouse embryo analysis; osteoblast culture; RANKL/OPG expression analysis; spleen cell co-culture osteoclastogenesis assay The American journal of pathology High 18669617
2009 CaMKII phosphorylates DLX5, increases its protein stability, and increases its osteoblastogenic transactivation activity; the CaMKII inhibitor KN-93 decreases osteogenic and transactivation activities of Dlx5. In vitro kinase assay; protein stability assay; transcriptional reporter assay; pharmacological inhibition Biochemical and biophysical research communications Medium 19393622
2010 AMPK activation (via AICAR or metformin) stimulates osteoblast differentiation through Smad1/5/8 phosphorylation → Dlx5 expression → Runx2 expression; siRNA knockdown of Dlx5 suppresses metformin-induced Runx2 expression, placing Dlx5 downstream of AMPK/Smad signaling and upstream of Runx2. AMPK activator/inhibitor pharmacology; dominant-negative AMPK; siRNA knockdown; BRE-Luc and Runx2-Luc reporter assays Biochemical and biophysical research communications Medium 21187071
2014 Dlx5 and Mef2 directly bind to a conserved 343-bp osteoblast-specific enhancer ~30 kb upstream of the Runx2 distal promoter (confirmed by ChIP); their binding sites are required for osteoblast-specific Runx2 expression in mice; other factors (Tcf7, Ctnnb1, Sp7, Smad1, Sox6) bind through protein-protein interactions. BAC reporter mouse; serial deletion; ChIP in primary osteoblasts; histone modification analysis; enhancer binding site mutagenesis in vivo Journal of bone and mineral research High 24692107
2014 DLX5 is a direct transcriptional target of the FGF8 locus and participates in a regulatory loop with p63 and Pin1: DLX5 activates FGF8 expression, while FGF8 counteracts Pin1-ΔNp63α interaction; Pin1 negatively regulates ΔNp63α protein stability via proteasomal degradation; p63 mutants associated with SHFM/EEC are resistant to Pin1 action. In vivo ChIP; luciferase reporter; co-immunoprecipitation; proteasome assay; mouse embryo analysis Human molecular genetics Medium 24569166
2011 Dlx5 identifies direct target genes in the inner ear by gene expression profiling of wild-type vs. Dlx5-null otic vesicles; ChIP confirms DLX5 directly binds promoters of Atbf1, Bmper, Large, Lrrtm1, Msx1, Ebf1, and Lhx1, with Bmper and Lrrtm1 being up-regulated upon Dlx5 overexpression, supporting BMP signaling as downstream of Dlx5 in the inner ear. Gene expression profiling (microarray); ChIP with Dlx5 antibody in overexpressing cell line; motif analysis Human molecular genetics Medium 21227998
2010 Hand2 represses Dlx5 and Dlx6 expression in the distal mandibular arch ectomesenchyme as part of a negative-feedback loop (Dlx5/6 first induce Hand2, which then represses Dlx5/6); failure to repress Dlx5/6 leads to upregulation of Runx2 and aberrant bone formation, and aglossia due to absent lateral lingual swelling. Conditional knockout mouse; genetic epistasis (Hand2 and Dlx5/6 compound mutants); in situ hybridization Development (Cambridge, England) High 21558373
2009 Dlx5 loss leads to reduced Fgf7 expression and expanded Shh signaling in the palatal mesenchyme; this expanded Shh signaling rescues palatal expansion and fusion in Msx1-null mice. Exogenous Fgf7 inhibits Shh signaling and reverses this rescue in Msx1/Dlx5 double knockout palates. Dlx5 null and Msx1/Dlx5 double-KO mouse analysis; exogenous Fgf7 treatment; in situ hybridization; genetic epistasis Development (Cambridge, England) High 19934017
2008 TGF-β signaling in cranial neural crest cells suppresses Dlx5 expression and maintains chondrogenic potential; conditional inactivation of Tgfbr2 in CNC cells leads to elevated Dlx5 expression and accelerated osteoprogenitor differentiation at the expense of chondrogenesis; deletion of Dlx5 in Tgfbr2 CNC conditional knockout mice rescues cartilage formation in the angular processes. Conditional knockout (Tgfbr2flox; Wnt1-Cre); Dlx5/Tgfbr2 compound conditional KO rescue; in situ hybridization; exogenous TGF-β treatment Developmental biology High 18684439
2017 Dlx5 in cranial neural crest cells controls FGF10 signaling to regulate interaction between CNC-derived cells and pharyngeal mesoderm-derived myoblasts during soft palate development; FGF10 pathway is downregulated in Dlx5 null mice and exogenous FGF10 rescues CNC cell proliferation and myogenic differentiation. Dlx5 null mouse analysis; exogenous FGF10 rescue; CNC-myoblast interaction analysis; proliferation and apoptosis assays Development (Cambridge, England) Medium 28982687
2016 DLX5 and DLX6 reciprocally inhibit BMP/HAND2-mediated activation of the Hand1 enhancer in the mandibular arch distal cap; DLX5/DLX6 homeodomain proteins thus exclude formation of the Hand1-positive distal cap domain from Dlx5/6-expressing proximal domains. Enhancer reporter assay; co-transfection with DLX5/6; genetic analysis in Dlx5/6 null embryos Proceedings of the National Academy of Sciences of the United States of America Medium 27335460
2021 DLX5 cooperates with the master transcription factor TP63 in regulating approximately 2000 enhancers and promoters in squamous cell carcinoma; DLX5 promoter gains active histone marks via SOX2-mediated activation in ESCC (vs. bivalent/silenced state in normal tissue); DLX5 silencing inhibits SCC viability in vitro and in vivo. ATAC-seq/ChIP-seq (bivalent chromatin analysis); computational ELMER analysis; shRNA knockdown; xenograft assay Nucleic acids research Medium 34370013
2015 Dlx5 regulates olfactory receptor neuron differentiation via miR-9 and miR-200 class microRNAs; Dlx5 null olfactory epithelium has reduced miR-9, miR-376a, and miR-200 class expression; miR-9 and miR-200 negatively regulate Foxg1 mRNA, and elevated Foxg1 (in the absence of these miRs) delays ORN differentiation and alters axon targeting in zebrafish. miRNA profiling; zebrafish miR-9/miR-200 depletion; Foxg1 mRNA quantification; reporter assays; Dlx5 null mouse olfactory epithelium analysis Molecular and cellular neurosciences Medium 25937343
2023 DLX5 directly binds the Col10a1 cis-enhancer (confirmed by dual-luciferase and ChIP assays) and promotes Col10a1 expression and chondrocyte hypertrophy; DLX5 cooperates with RUNX2, as adjacent DLX5 and RUNX2 binding sites exist within the Col10a1 enhancer; DLX5 and COL10A1 are co-upregulated in a murine OA model. Dual-luciferase reporter assay; ChIP; siRNA knockdown and overexpression; murine OA model Genes & diseases Medium 37492739
2018 STAT5A negatively regulates Dlx5 expression in bone marrow-derived stromal cells; STAT5A deletion increases trabecular and cortical bone mass and enhances fracture healing by promoting osteogenesis, establishing a STAT5A-DLX5 regulatory axis in osteogenesis. STAT5A siRNA knockdown; STAT5A knockout mouse analysis (bone morphometry, fracture model); in vitro osteogenesis assays Cell death & disease Medium 30429452
2018 cAMP/PKA signaling inhibits Dlx5 expression in preadipocytes via CREB-mediated induction of C/EBPβ, which directly binds site-1 (−517 to −510 bp) in the Dlx5 promoter to suppress transcription; C/EBPβ knockdown rescues Dlx5 expression in IBMX-treated cells. Luciferase reporter assay; ChIP; siRNA knockdown (C/EBPβ); forced CREB and C/EBPβ expression International journal of molecular sciences Medium 30322210
2010 DLX5 directly binds and activates the NOTCH1 promoter (identified by JASPAR analysis and confirmed by dual-luciferase reporter assay), and knockdown of DLX5 reduces NOTCH1, NICD, and HES1 expression; NOTCH1 overexpression rescues proliferation and migration inhibition caused by DLX5 knockdown in osteosarcoma cells. Dual-luciferase reporter assay; siRNA knockdown; NOTCH1 overexpression rescue; xenograft model American journal of cancer research Medium 34249467
2006 Dlx5 and Dlx6 control vestibular cell fate specification by restricting Pax2 and activating Gbx2 and Bmp4 expression domains in the otic epithelium; otic induction initiates normally in Dlx5/6 null embryos but dorsal otic derivatives fail to form. Dlx5/6 double knockout mouse analysis; in situ hybridization for Pax2, Gbx2, Bmp4 Genesis (New York, N.Y. : 2000) High 16900517
2011 Dlx5 and Dlx6 are required for uterine adenogenesis; conditional inactivation of Dlx5/6 in the endometrium (using Pgr-Cre) results in sterility, very few uterine glands, and reduced expression of Foxa2 and Msx1, demonstrating a role for Dlx5/6 in gland formation and epithelial remodeling. Conditional knockout (Pgr-Cre; Dlx5/6 flox); uterine histology; gene expression analysis Human molecular genetics Medium 26512061
2000 A highly conserved enhancer in the Dlx5/Dlx6 intergenic region is bound and activated by DLX proteins (confirmed by cotransfection and DNA-protein binding assays); this enhancer drives forebrain expression of transgenes recapitulating Dlx5/6 patterns, and its activity is drastically reduced in Dlx1/2 double mutant mice, establishing Dlx1/2-mediated cross-regulation of Dlx5/6 in the forebrain. Transgenic reporter assay (mouse and zebrafish); Dlx1/2 double mutant analysis; cotransfection reporter assay; DNA-protein binding assay (EMSA) The Journal of neuroscience High 10632600
2010 A single nucleotide polymorphism (SNP) found in an autistic proband within the I56i ultraconserved enhancer of Dlx5/Dlx6 reduces DLX protein binding affinity (confirmed by binding assay) and decreases enhancer activity predominantly in the medial and caudal ganglionic eminences; Gtf2i (deleted in Williams-Beuren syndrome) is identified as a novel regulator of Dlx gene expression by affinity purification using the I56i sequence. Transgenic reporter assay; in vitro protein-binding assay; affinity purification/mass spectrometry Development (Cambridge, England) Medium 20702565
2010 Dlx5 and Dlx6 are required for development of parvalbumin-expressing cortical interneurons; loss of Dlx5 or Dlx5/6 preferentially reduces mature parvalbumin+ interneurons, increases their dendritic branching, and is associated with reduced CXCR4 expression and defective tangential migration; Dlx5/6+/- mice show spontaneous electrographic seizures and reduced gamma oscillations. Dlx5 and Dlx5/6 conditional knockout; interneuron transplantation assay; EEG recording; immunohistochemistry; migration analysis The Journal of neuroscience High 20392955
2019 GABAergic neuron-specific inactivation of Dlx5/6 (using Vgat-Cre) reduces anxiety-like behaviors and obsessive-compulsive activities and results in 33% longer median lifespan; 20-month-old mutants show 25% body weight reduction with marked reduction of white and brown adipose tissue, implicating GABAergic Dlx5/6 signaling in metabolic regulation and longevity. Conditional knockout (Vgat-Cre; Dlx5/6 flox); behavioral testing; body composition analysis; survival analysis Aging Medium 31514171

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 438 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 348 12815054
2002 The Dlx5 and Dlx6 homeobox genes are essential for craniofacial, axial, and appendicular skeletal development. Genes & development 338 12000792
2003 BMP-2-induced Osterix expression is mediated by Dlx5 but is independent of Runx2. Biochemical and biophysical research communications 327 12963046
1999 Dlx5 regulates regional development of the branchial arches and sensory capsules. Development (Cambridge, England) 287 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 276 10632600
1999 DLX-1, DLX-2, and DLX-5 expression define distinct stages of basal forebrain differentiation. The Journal of comparative neurology 238 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 229 15456894
2007 BMP-2 induces Osterix expression through up-regulation of Dlx5 and its phosphorylation by p38. The Journal of biological chemistry 184 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) 155 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
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
2004 Segregation of lens and olfactory precursors from a common territory: cell sorting and reciprocity of Dlx5 and Pax6 expression. Developmental biology 139 15223343
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 101 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 86 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
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
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) 65 19934017
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) 58 20702565
2017 Disturbed Placental Imprinting in Preeclampsia Leads to Altered Expression of DLX5, a Human-Specific Early Trophoblast Marker. Circulation 57 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 51 21045156
2012 Functional characterization of tissue-specific enhancers in the DLX5/6 locus. Human molecular genetics 50 22914741
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
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 48 25937343
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 43 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 38 19497851
2020 DLX5 and HOXC8 enhance the chondrogenic differentiation potential of stem cells from apical papilla via LINC01013. Stem cell research & therapy 36 32631410
2019 Dlx5 and Dlx6 expression in GABAergic neurons controls behavior, metabolism, healthy aging and lifespan. Aging 36 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 36 19707792
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 32 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
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
2015 Dlx5 and Dlx6 control uterine adenogenesis during post-natal maturation: possible consequences for endometriosis. Human molecular genetics 28 26512061
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 28 24496061
2017 The Dlx5-FGF10 signaling cascade controls cranial neural crest and myoblast interaction during oropharyngeal patterning and development. Development (Cambridge, England) 27 28982687
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
2013 BMP-mediated functional cooperation between Dlx5;Dlx6 and Msx1;Msx2 during mammalian limb development. PloS one 25 23382810
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
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
2021 Activation of bivalent factor DLX5 cooperates with master regulator TP63 to promote squamous cell carcinoma. Nucleic acids research 22 34370013
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 21 33002480
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
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 21 25332435
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
2009 Dlx5 Is a cell autonomous regulator of chondrocyte hypertrophy in mice and functionally substitutes for Dlx6 during endochondral ossification. PloS one 20 19956613
2023 DLX5 promotes Col10a1 expression and chondrocyte hypertrophy and is involved in osteoarthritis progression. Genes & diseases 19 37492739
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 19 25467232
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
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2018 Deletion of a Long-Range Dlx5 Enhancer Disrupts Inner Ear Development in Mice. Genetics 17 29301908
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
2021 DLX5 promotes osteosarcoma progression via activation of the NOTCH signaling pathway. American journal of cancer research 16 34249467
2018 Probing the origin of matching functional jaws: roles of Dlx5/6 in cranial neural crest cells. Scientific reports 16 30297736