Affinage

DLX3

Homeobox protein DLX-3 · UniProt O60479

Length
287 aa
Mass
31.7 kDa
Annotated
2026-04-28
100 papers in source corpus 41 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DLX3 is a homeodomain transcription factor that orchestrates differentiation programs in ectodermal, skeletal, and dental tissues by functioning as a context-dependent transcriptional activator or repressor. DLX3 recognizes a 5'-TAATT-3' consensus motif via its α3 helix and L1 loop (PMID:36012753), directly regulating promoters of Runx2, Dspp, Dkk1, osteocalcin, ion transporters, and AhR in osteoblasts, odontoblasts, ameloblasts, and keratinocytes (PMID:17060321, PMID:22351765, PMID:30524303, PMID:27760456); it interacts with Runx2, Osx, p53, GCM1, and Smad6 to modulate transcriptional output (PMID:15456894, PMID:28883412, PMID:26522723, PMID:28515447, PMID:16687405). DLX3 activity is tuned by multiple post-translational modifications—PKCα phosphorylation at S138 reduces DNA binding, PKA phosphorylation at S10 and Akt1 phosphorylation enhance stability and activity, MAST4 phosphorylation of NLS residues controls nuclear entry, SUMOylation at K112 augments transcriptional output, MDM2-mediated monoubiquitination enhances activity while CHIP-catalyzed K63-polyubiquitination promotes degradation (PMID:11343707, PMID:24924519, PMID:22885182, PMID:38945953, PMID:21268066, PMID:35220830, PMID:37213079). Conditional deletion causes placental failure, alopecia with loss of hair follicle differentiation, IL-17-driven skin inflammation with STAT3 activation, defective dentin formation, and disrupted enamel mineralization, while the tricho-dento-osseous (TDO) frameshift mutation abolishes DNA binding and exerts a dominant-negative effect on wild-type DLX3 (PMID:9874789, PMID:18684741, PMID:21709238, PMID:29246798, PMID:22351765, PMID:18492670).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1999 High

    The fundamental requirement for DLX3 in mammalian development was established when its deletion caused embryonic lethality from placental labyrinthine trophoblast failure, revealing DLX3 as essential for placental morphogenesis and identifying Esx1 as a downstream target.

    Evidence Targeted gene knockout in mice with histological and expression analysis

    PMID:9874789

    Open questions at the time
    • Mechanism by which DLX3 regulates trophoblast differentiation beyond Esx1 regulation
    • Whether DLX3 acts cell-autonomously in trophoblasts
  2. 1999 High

    DLX3 was shown to act as a transcriptional activator in keratinocytes with calcium-dependent induction, and simultaneously as an antineural transcriptional regulator in Xenopus ectoderm, establishing its context-dependent transcriptional roles across species.

    Evidence Dlx3 promoter deletion/mutagenesis in keratinocytes; overexpression in Xenopus embryos with neural marker analysis

    PMID:10433834 PMID:10473625

    Open questions at the time
    • Whether antineural function in Xenopus reflects a conserved mammalian mechanism
    • Identity of direct DLX3 target genes mediating neural repression
  3. 2000 High

    The bipartite NLS within DLX3's homeodomain was identified as a regulatory hub required for nuclear targeting, DNA binding, transcriptional activation, and interaction with Msx1, with phosphorylation of NLS residues abrogating all these functions.

    Evidence GFP-fusion imaging, mutagenesis, yeast one-hybrid, and pulldown assays

    PMID:11058088

    Open questions at the time
    • Identity of the kinase(s) targeting NLS residues in vivo (later resolved by MAST4 discovery)
    • Structural basis of NLS phosphorylation-dependent inhibition
  4. 2001 High

    PKCα was identified as the kinase phosphorylating DLX3 at S138 within the homeodomain, partially inhibiting DNA binding during calcium-dependent keratinocyte differentiation—the first specific post-translational modification linked to DLX3 regulation.

    Evidence In vitro kinase assay, site-directed mutagenesis, EMSA, PKC inhibitor treatment

    PMID:11343707

    Open questions at the time
    • In vivo significance of S138 phosphorylation for epidermal differentiation
    • Whether PKCα-DLX3 phosphorylation is reversible and by which phosphatase
  5. 2002 High

    The upstream signaling pathway activating DLX3 transcription was defined: BMP-2 induces Dlx3 through Smad1/Smad4 binding to a GCAT motif in the Dlx3 promoter, establishing BMP-Smad signaling as a primary inducer of DLX3.

    Evidence Recombinant Smad1/Smad4 gel shift, promoter mutagenesis, reporter assays in keratinocytes

    PMID:11788714

    Open questions at the time
    • Whether other BMP-responsive Smads can substitute
    • Tissue-specific differences in BMP-mediated Dlx3 induction
  6. 2004 High

    A temporal chromatin switch at osteogenic promoters was discovered: DLX3 replaces Msx2 at the osteocalcin promoter post-proliferatively, and DLX3 physically interacts with Runx2 to modulate its transcriptional activity, defining DLX3 as a chromatin-level regulator of osteoblast gene expression.

    Evidence ChIP, co-immunoprecipitation, RNAi, promoter deletion in osteoprogenitor cells

    PMID:15456894

    Open questions at the time
    • Whether DLX3-Runx2 interaction is direct or requires bridging factors
    • Structural basis of the Msx2-to-DLX3 promoter switch
  7. 2006 High

    DLX3 was positioned upstream of Runx2 in the osteogenic hierarchy: forced DLX3 expression in Runx2-null cells induced Runx2, osteocalcin, and alkaline phosphatase, while Smad6 was identified as a negative regulator that directly binds DLX3 and blocks its DNA binding in trophoblasts.

    Evidence Epistasis via Runx2-null rescue, ChIP, promoter mutagenesis; reciprocal IP and EMSA for Smad6 interaction

    PMID:16687405 PMID:17060321

    Open questions at the time
    • Whether DLX3 directly binds the Runx2 promoter or acts through intermediate factors (later resolved by ChIP-seq)
    • Stoichiometry of Smad6-DLX3 complex
  8. 2008 High

    Two critical in vivo functions were established: conditional epidermal Dlx3 ablation caused alopecia by disrupting Wnt→Dlx3→Hoxc13/Gata3 hair follicle differentiation cascade, while the TDO frameshift mutant was shown to form complexes with wild-type DLX3 and exert dominant-negative effects, explaining the autosomal dominant inheritance of tricho-dento-osseous syndrome.

    Evidence K14-Cre conditional KO with pathway epistasis; EMSA, inducible cell lines, co-expression reporter assays for TDO mutant

    PMID:18492670 PMID:18684741

    Open questions at the time
    • Whether TDO mutant-WT heterodimer has altered chromatin occupancy genome-wide
    • Mechanism of BMP signaling loss in Dlx3-null bulge stem cells
  9. 2011 High

    SUMOylation at K112 was identified as a positive regulatory modification that enhances DLX3 transcriptional activity without affecting nuclear localization or DNA binding, while epidermal Dlx3 loss was linked to IL-17-dependent cutaneous inflammation, revealing DLX3 as a skin immune gatekeeper.

    Evidence Site-directed mutagenesis with EMSA and reporter assays; conditional KO with FACS, cytokine analysis, expression profiling

    PMID:21268066 PMID:21709238

    Open questions at the time
    • Identity of the SUMO E3 ligase targeting DLX3 K112
    • Whether inflammatory phenotype is cell-autonomous or secondary to barrier disruption
  10. 2012 High

    DLX3 was shown to directly bind and activate the Dspp promoter in odontoblasts (ChIP-seq), establishing a Dlx3→Dspp pathway essential for dentin formation, while Akt1 phosphorylation was found to increase DLX3 stability and activity during BMP2-induced osteogenesis.

    Evidence Neural crest-specific conditional KO, ChIP-seq, luciferase assays; kinase assay with Akt inhibitor treatment

    PMID:22351765 PMID:22885182

    Open questions at the time
    • Specific Akt1 phosphorylation site(s) on DLX3 not mapped
    • Whether Dspp is a direct or indirect target in ameloblasts versus odontoblasts
  11. 2014 High

    Genome-wide ChIP-seq in conditional KO models defined the direct DLX3 transcriptional program in bone (Dlx5, Dlx6, Runx2, Sp7, Ibsp), revealed that DLX3 loss paradoxically increases bone mass through compensatory DLX5/RUNX2 occupancy, and PKA was identified as phosphorylating DLX3 at S10 to enhance its stability and activity.

    Evidence Two independent conditional KOs (Prx1-Cre, OCN-Cre), RNA-seq, ChIP-seq; in vitro PKA kinase assay with S10A mutagenesis

    PMID:24924519 PMID:24948010

    Open questions at the time
    • How DLX3/DLX5 balance is maintained in normal osteoblasts
    • Whether S10 phosphorylation cross-talks with K112 SUMOylation
  12. 2015 High

    DLX3 was linked to tumor suppression: it physically interacts with p53 on the p21 promoter to enforce G1-S arrest, and its loss activates ERK signaling and promotes keratinocyte migration, positioning DLX3 as an antiproliferative factor in skin.

    Evidence Co-IP, ChIP on p21 promoter, cell cycle analysis, wound closure assay, mouse carcinogenesis model

    PMID:26522723

    Open questions at the time
    • Whether DLX3 loss is a driver or passenger in squamous cell carcinoma
    • Whether DLX3-p53 interaction occurs in non-keratinocyte contexts
  13. 2017 High

    Multiple studies consolidated DLX3's tissue-specific programs: in epidermis, a PKCα-DLX3 feedback loop controls differentiation and STAT3 signaling; in placenta, DLX3 antagonizes GCM1 on the PGF promoter; in ameloblasts, DLX3 directly regulates ion transporters and carbonic anhydrases controlling enamel pH oscillations; in odontoblasts, DLX3 cooperates with Osx to activate Dspp.

    Evidence ChIP-seq in suprabasal keratinocytes with transgenic/cKO models; inducible cKO with RNA-seq and STAT3 inhibitor rescue; Co-IP/ChIP/mutagenesis for GCM1 and Osx interactions; dental epithelium cKO with transcriptomics

    PMID:27760456 PMID:28186503 PMID:28515447 PMID:28883412 PMID:29246798

    Open questions at the time
    • Structural basis of DLX3-GCM1 antagonism
    • Whether STAT3 activation is a direct transcriptional consequence of DLX3 loss
  14. 2019 High

    DLX3 was found to activate Dkk1 transcription to inhibit Wnt/β-catenin signaling in dental pulp cells, while MDM2 was identified as monoubiquitinating DLX3 to enhance its Dspp-activating function in odontoblasts, revealing opposing ubiquitin-dependent regulatory mechanisms.

    Evidence ChIP and mutagenesis of Dkk1 promoter; Co-IP and ubiquitination assays with MDM2 in dental papilla cells

    PMID:30524303 PMID:31847675

    Open questions at the time
    • Which lysine residue(s) are monoubiquitinated by MDM2
    • Whether DLX3 regulation of Wnt via Dkk1 operates in bone
  15. 2022 High

    The competing E3 ligase mechanism was resolved: MDM2 monoubiquitinates DLX3 via its C-terminal domain to promote transcriptional activity, while CHIP catalyzes K63-polyubiquitination leading to proteasomal degradation; NMR structural analysis simultaneously defined the α3 helix and L1 loop as the DNA-recognition interface.

    Evidence Conditional KO (Dmp1-Cre;Mdm2), in situ PLA, Co-IP, ubiquitination assays, domain mutagenesis; NMR chemical shift perturbation with varying salt conditions

    PMID:35220830 PMID:36012753

    Open questions at the time
    • Whether the MDM2/CHIP balance is regulated by upstream signals
    • Full atomic-resolution structure of DLX3 homeodomain-DNA complex not yet solved
  16. 2024 High

    MAST4 kinase was identified as the NLS-targeting kinase that phosphorylates three residues in DLX3's NLS to promote nuclear translocation and target gene expression during ameloblast maturation, resolving the long-standing question of which kinase controls NLS-dependent nuclear entry.

    Evidence Mast4 KO mice, Co-IP, phosphorylation assay, nuclear localization analysis, target gene expression

    PMID:38945953

    Open questions at the time
    • Whether MAST4 regulation of DLX3 operates in osteoblasts or keratinocytes
    • Interplay between MAST4 phosphorylation and PKCα S138 phosphorylation

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the full crystal/cryo-EM structure of DLX3 in complex with DNA and partner transcription factors; how the multiple post-translational modifications (phosphorylation, SUMOylation, mono- vs. polyubiquitination) are integrated temporally during differentiation; and whether DLX3's tumor-suppressive role in skin extends to other epithelia.
  • No atomic-resolution structure of full-length DLX3 or DLX3-partner complexes
  • Systematic analysis of PTM cross-talk in a single cellular context not performed
  • DLX3 tumor-suppressive function not validated beyond skin SCC

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 15 GO:0003677 DNA binding 13
Localization
GO:0005634 nucleus 5
Pathway
R-HSA-74160 Gene expression (Transcription) 12 R-HSA-1266738 Developmental Biology 9 R-HSA-392499 Metabolism of proteins 8 R-HSA-162582 Signal Transduction 6
Partners
GCM1MDM2MSX1RUNX2SMAD6SP7STUB1TP53

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Targeted deletion of Dlx3 in mice results in embryonic lethality due to placental failure, with defects in the labyrinthine trophoblast layer and down-regulation of Esx1 expression, establishing Dlx3 as required for placental morphogenesis and Esx1 maintenance. Gene knockout (targeted deletion) with in situ hybridization and marker gene expression analysis Proceedings of the National Academy of Sciences of the United States of America High 9874789
1999 DLX3 acts as a transcriptional activator in keratinocytes; its proximal promoter is controlled by NF-Y binding to a CCAAT box motif and an Sp1-binding site, with calcium-dependent induction mediated by elements at +30 to +60. Serial deletion analysis, gel retardation assays, mutational analysis of Dlx3 promoter in primary mouse keratinocytes The Journal of biological chemistry High 10473625
1999 Dlx3 and Msx1 function as antineural transcriptional regulators in Xenopus anterior neural plate; Dlx3 represses panneural markers (Zic family, BF-1) while permitting anterior neural plate gene expression, distinct from Msx1's activity. Overexpression in Xenopus embryos, reporter assays, analysis of gene expression boundaries Developmental biology Medium 10433834
2000 DLX3 contains a bipartite nuclear localization signal (NLS) within its homeodomain that is required for nuclear targeting, DNA binding, transcriptional activation, and interaction with Msx1 protein; phosphorylation or mutation of the NLS abrogates these functions. GFP fusion live-cell imaging, mutational analysis, yeast one-hybrid transactivation assay, in vitro binding (pulldown) with Msx1 Journal of cell science High 11058088
2000 Early expression of Dlx3 in ventral Xenopus ectoderm is repressed by beta-catenin signaling, independent of Xnr3 or chordin induction, establishing a mechanism by which dorsal-ventral patterning restricts Dlx3 and creates pro-neural bias in dorsal ectoderm. Epistasis in Xenopus embryos, gain/loss of beta-catenin function, expression analysis of Dlx3 Mechanisms of development Medium 10704847
2001 PKC phosphorylates Dlx3 protein at serine S138 within the homeodomain, partially inhibiting Dlx3-DNA complex formation; PKCα is the primary isoform responsible, and this phosphorylation is induced during calcium-dependent keratinocyte differentiation. In vitro kinase assay, deletion and site-directed mutagenesis, EMSA (electrophoresis mobility shift assay), PKC inhibitor treatment of keratinocyte nuclear extracts FEBS letters High 11343707
2002 BMP-2 transcriptionally induces Dlx3 through Smad1 and Smad4 binding to a GCAT motif in the Dlx3 promoter (-1917 to -1747); mutation of this Smad1/Smad4 binding site abolishes BMP-2-mediated transcriptional activation. Promoter deletion/mutational analysis, gel shift assay with recombinant Smad1/Smad4, supershift assay with keratinocyte nuclear extracts, reporter assays in keratinocytes Nucleic acids research High 11788714
2004 During osteoblast differentiation, there is a temporal chromatin switch: the osteocalcin (OC) gene promoter is occupied by Msx2 in proliferating cells (repression), and then Dlx3 and Dlx5 are recruited post-proliferatively to initiate transcription; Dlx3 physically interacts with Runx2 (interaction domain mapped to Runx2 aa 376-432) and this reduces Runx2-mediated transcription. Chromatin immunoprecipitation (ChIP), co-immunoprecipitation, promoter deletion analysis, RNA interference knockdown, overexpression in osteoprogenitor cells Molecular and cellular biology High 15456894
2006 BMP2 induces DLX3 which then activates Runx2 gene transcription; in Runx2-null cells, DLX3 forced expression is sufficient to induce Runx2, osteocalcin, and alkaline phosphatase, defining DLX3 as an osteogenic regulator upstream of and independent of RUNX2; MSX2 and CDP/cut repress while DLX3 and DLX5 activate Runx2 promoter via multiple homeodomain (HD) elements. siRNA knockdown, forced expression in Runx2-null cells, ChIP, Runx2 promoter mutagenesis, reporter assays The Journal of biological chemistry High 17060321
2006 Smad6 physically interacts with DLX3 (interaction mapped to residues 80-163 of DLX3 including part of the homeodomain) in human trophoblast cells and inhibits DLX3 DNA binding to the Esx1 promoter, thereby repressing DLX3-dependent Esx1 transcription. Immunocytochemistry, immunoprecipitation, in vitro protein interaction mapping, EMSA, siRNA knockdown of Smad6, luciferase reporter assay The Journal of biological chemistry High 16687405
2007 Dlx3 is a downstream transcriptional target of p63; mutations in the SAM domain of p63 associated with AEC ectodermal dysplasia abrogate Dlx3 transcription, whereas EEC, LMS, and SHFM mutations do not, placing DLX3 in the p63 transcriptional pathway for ectoderm development. Reporter assays, epistasis via p63 mutant overexpression, expression analysis in p63-mutant context Development (Cambridge, England) Medium 17164413
2008 The TDO-associated frameshift DLX3(TDO) mutant protein localizes to the nucleus but cannot bind canonical Dlx3 DNA binding sites (EMSA); its C-terminal frameshift domain causes loss of DNA binding; however DLX3(TDO) can form a complex with DLX3(WT) that binds DNA, and DLX3(TDO) has a dominant-negative effect reducing WT transcriptional activity. Immunocytochemistry, EMSA, tetracycline-inducible osteoblast and keratinocyte cell lines, co-expression experiments, reporter assays The Journal of biological chemistry High 18492670
2008 Conditional epidermal ablation of Dlx3 results in complete alopecia due to failure of hair shaft and inner root sheath differentiation; Dlx3 is positioned downstream of Wnt signaling and upstream of Hoxc13 and Gata3 in a transcriptional cascade regulating hair follicle differentiation; loss of Dlx3 in telogen bulge stem cells abolishes BMP signaling, preventing hair follicle cycle re-initiation. Conditional knockout (K14-Cre), immunostaining, epistasis with Wnt/BMP pathway components, expression analysis of downstream transcription factors Development (Cambridge, England) High 18684741
2009 DLX3 triggers p63 protein degradation via a proteasome-dependent pathway involving Raf1 phosphorylation; DLX3-mediated degradation requires specific Thr397 and Ser383 residues on ΔNp63α; DLX3 is unable to promote p63 degradation in Raf1-depleted cells or upon pharmacological Raf1 inhibition. Transient expression/co-expression, Raf1 knockdown MEF cells, pharmacological Raf1 inhibition, proteasome inhibitor treatment, mutant p63 resistance analysis Cell cycle (Georgetown, Tex.) Medium 19282665
2011 DLX3 is SUMOylated by SUMO1 at lysine K112 in its N-terminal domain; SUMOylation does not prevent nuclear localization or DNA binding but positively enhances DLX3 transcriptional activity, as K112R mutant shows significantly reduced transcriptional activity. Site-directed mutagenesis, co-expression SUMOylation assay, immunocytochemistry, EMSA, luciferase reporter assay Journal of cellular biochemistry High 21268066
2011 Epidermal ablation of Dlx3 (K14cre;Dlx3) leads to epidermal hyperproliferation, abnormal keratinocyte differentiation, and IL-17-associated cutaneous inflammation with accumulation of IL-17-producing T cells; Dlx3-null keratinocytes trigger cytokine production linked to inflammatory responses. Conditional knockout, immunostaining, FACS, cytokine analysis, gene expression profiling Proceedings of the National Academy of Sciences of the United States of America High 21709238
2012 Neural crest deletion of Dlx3 results in hypoplastic dentin and impaired odontoblast differentiation; DLX3 directly binds the Dspp promoter in vivo (ChIP-seq) and positively regulates Dspp transcription (luciferase assay), establishing a Dlx3→Dspp regulatory pathway essential for dentin formation. Conditional knockout (neural crest-specific Cre), ChIP-seq, luciferase reporter assay, histology The Journal of biological chemistry High 22351765
2012 Hairless (Hr) protein down-regulates Dlx3 mRNA expression through suppression of Dlx3 promoter activity; Dlx3 in turn regulates IRS keratin expression, establishing an Hr→Dlx3→IRS keratins regulatory cascade in hair follicle inner root sheath formation. Hr mutant mouse (Hr(Hp)/Hr(Hp)) analysis, Dlx3 promoter reporter assay, expression analysis of Dlx3 and IRS keratins The Journal of biological chemistry Medium 22442153
2012 Akt1 phosphorylates Dlx3, increasing its protein stability, DNA binding affinity, and transcriptional activity during osteoblast differentiation; BMP2 increases Dlx3 protein levels in an Akt1 activity-dependent manner. Kinase assay (phosphorylation), Akt inhibitor treatment, co-expression, reporter assay, western blot for protein stability Biochemical and biophysical research communications Medium 22885182
2014 In vivo conditional loss of DLX3 in mesenchymal cells and osteoblasts results in increased bone mass accrual, increased osteoblast activity, and altered expression of bone matrix genes; RNA-seq and ChIP-seq show DLX3 directly regulates Dlx5, Dlx6, Runx2, Sp7, Ibsp, Enpp1, Mepe, and Opg; removal of DLX3 increases DLX5 occupancy and earlier RUNX2 occupancy on the osteocalcin promoter. Conditional knockout (Prx1-Cre, OCN-Cre), micro-CT, dynamic bone formation analysis, RNA-seq, ChIP-seq Cell death and differentiation High 24948010
2014 BMP-2 induction of Dlx3 transcription in osteoblasts is mediated by p38/Smad5 signaling; Smad5 and p38 activate Dlx3 promoter via two TGTCT Smad5 binding sites (-698 to -368); p38 activation is required for BMP-2-induced Smad5 phosphorylation and nuclear translocation, revealing a p38/Smad5 cross-talk. Smad5 and p38 knockdown/activation, EMSA, ChIP, Dlx3 promoter deletion and mutagenesis, reporter assay in MC3T3-E1 cells Journal of cellular physiology High 24647893
2014 PKA phosphorylates Dlx3 at serine 10 (S10), increasing Dlx3 protein stability, DNA binding, and transcriptional activity during BMP2-induced osteoblast differentiation; S10A substitution reduces PKA-mediated phosphorylation and abrogates PKA regulation of Dlx3 function. In vitro kinase assay, site-directed mutagenesis (S10A), PKA activator/inhibitor treatment, reporter assay, western blot Journal of cellular biochemistry High 24924519
2015 DLX3 and p53 physically interact on the p21 promoter to enhance p21 expression; elevated DLX3 in keratinocytes produces G1-S blockade; DLX3 loss promotes ERK activation and mitogenic phenotype; DLX3 re-expression attenuates SCC cell migration. Co-immunoprecipitation, ChIP on p21 promoter, genetic knockdown/overexpression, cell cycle analysis, wound closure assay, mouse carcinogenesis model Oncogene High 26522723
2015 KDM4B histone demethylase directly occupies regulatory regions of the Dlx3 locus (reducing H3K9me3) and is required for Dlx3 expression and otic vesicle invagination in chick; DLX3 expression rescues the invagination defect caused by KDM4B knockdown. In vivo ChIP in chick embryos, KDM4B knockdown/rescue, DLX3 rescue of KDM4B KD phenotype, catalytically dead mutant control The Journal of cell biology High 26598618
2015 Estrogen receptor α (ER-α) positively regulates Dlx3 transcription during BMP2-induced osteoblast differentiation and physically interacts with Dlx3, increasing its transcriptional activity and DNA binding affinity in a ligand-independent manner. Reporter assay, co-immunoprecipitation, EMSA, BMP2 induction with ER-α overexpression Molecules and cells Medium 26674964
2017 DLX3 and GCM1 independently activate PGF promoter, but co-overexpression leads to antagonism; DLX3 physically interacts with GCM1 via its homeodomain and inhibits GCM1 transactivation activity; both factors co-localize at the PGF promoter regulatory region (ChIP). Overexpression/knockdown, luciferase reporter with promoter deletion/mutagenesis, ChIP, immunoprecipitation, mammalian one-hybrid assay Scientific reports High 27996093 28515447
2017 DLX3 expression and downstream signaling depend on PKCα activity in skin; PKCα activates DLX3 expression and ChIP-seq shows DLX3 binds proximal promoters of cell cycle, structural, and differentiation genes in suprabasal keratinocytes; a DLX3-PKCα feedback loop regulates epidermal homeostasis. K5-PKCα transgenic mice, DLX3 conditional KO, ChIP-seq in primary suprabasal keratinocytes, PKC inhibitor treatment, transcriptome analysis Cell death and differentiation High 28186503
2017 In odontoblasts, BMP-2 stimulates nuclear translocation of both Dlx3 and Osx; Osx is a downstream target of Dlx3; both Dlx3 and Osx bind the Dspp promoter (EMSA and ChIP), two Dlx3 binding sites and one Osx site identified; Dlx3 and Osx physically interact (co-IP), cooperating to activate Dspp transcription. EMSA, ChIP, co-immunoprecipitation, luciferase reporter assays, site-directed mutagenesis of Dspp promoter, in vitro and in vivo BMP-2 treatment Scientific reports High 28883412
2017 DLX3 ablation in keratinocytes results in STAT3 activation; DLX3 deletion upregulates proinflammatory cytokines and STAT3-related genes; topical STAT3 inhibition attenuates the immune phenotype of DLX3-null skin, establishing DLX3 as a regulator of STAT3 signaling network in skin homeostasis. Tamoxifen-inducible conditional KO, RNA-seq transcriptome profiling, topical STAT3 inhibitor treatment, immunostaining The Journal of investigative dermatology High 29246798
2017 DLX3 directly activates aryl hydrocarbon receptor (AhR) promoter by binding to a regulatory region ~5.5 kb upstream of the AhR transcription start site, enhancing AhR activity in NK cells. Reporter assay, promoter binding analysis, expression correlation in murine and human NK cells Biochemistry and biophysics reports Medium 27777986
2017 DLX3 regulates enamel mineralization by controlling expression of ion transporters and carbonic anhydrases (not enamel matrix proteins); DLX3 directly binds proximal promoters of affected ion transporter/carbonic anhydrase genes (ChIP-seq); loss of DLX3 disrupts pH oscillations during enamel maturation. Conditional KO in dental epithelium, transcriptomic analysis, ChIP-seq on rat enamel organ, pH staining histology Journal of bone and mineral research High 27760456
2019 Mdm2 E3 ubiquitin ligase physically interacts with DLX3 (co-immunoprecipitation) in the nucleus of odontoblasts and monoubiquitinates DLX3, enhancing Dspp expression and promoting odontoblast-like differentiation; simultaneously Mdm2 polyubiquitinates and degrades p53 to relieve its inhibition of differentiation. Co-immunoprecipitation, double immunofluorescence, ubiquitination assay, siRNA knockdown, overexpression in dental papilla cells Journal of dental research High 31847675
2019 DLX3 directly binds the Dkk1 promoter and stimulates its expression, thereby inhibiting Wnt/β-catenin signaling and suppressing proliferation of human dental pulp cells; two DLX3 responsive elements in the Dkk1 promoter were identified by luciferase reporter and ChIP assays. Luciferase reporter assay, ChIP, site-directed mutagenesis of Dkk1 promoter, DLX3 overexpression/knockdown Frontiers in physiology High 30524303
2019 DLX3 promotes osteogenic differentiation of BMSCs through the Wnt/β-catenin pathway by decreasing H3K27me3 enrichment at the DKK4 promoter, thereby increasing DKK4 expression; DLX3 knockdown reduces H3K27me3 at DKK4 promoter as shown by ChIP-qPCR. DLX3 overexpression/knockdown via lentivirus, ChIP-qPCR for H3K27me3 at DKK4 promoter, Wnt pathway analysis Biochemical and biophysical research communications Medium 31202458
2022 Nuclear Mdm2 interacts with DLX3 via DLX3's C-terminal domain (in situ PLA and Co-IP in vivo), and monoubiquitinates DLX3, promoting its transcriptional activity on Dspp and odontoblast differentiation; CHIP E3 ligase competes with Mdm2 by catalyzing K63 polyubiquitination of DLX3 leading to proteasomal degradation, thereby inhibiting odontoblast differentiation. Conditional KO (Dmp1-Cre;Mdm2), in situ proximity ligation assay (PLA), Co-IP, ubiquitination assay, Nutlin-3a treatment, domain deletion mutagenesis Journal of dental research High 35220830
2023 CHIP E3 ubiquitin ligase interacts with DLX3 and induces K63 polyubiquitination leading to proteasomal degradation of DLX3, inhibiting odontoblast differentiation; CHIP competes with MDM2 (monoubiquitination) for DLX3 modification; CHIP knockout mice show increased dentin formation and odontoblast marker expression. CHIP conditional KO (Stub1 KO), ectopic expression, knockdown, ubiquitination assay, Co-IP, histology Development (Cambridge, England) High 37213079
2022 NMR chemical shift perturbation demonstrates that DLX3 homeodomain selectively recognizes consensus DNA (5'-TAATT-3') through its α3 helix and L1 loop regions; DNA binding exhibits unique dynamic properties modulated by salt concentration. NMR chemical shift perturbation, imino proton spectra, varying salt conditions International journal of molecular sciences High 36012753
2024 MAST4 kinase directly binds DLX3 and phosphorylates three residues within DLX3's nuclear localization site (NLS), promoting nuclear translocation of DLX3; MAST4-mediated phosphorylation controls transcription of DLX3 target genes (carbonic anhydrases and ion transporters) during ameloblast maturation. Mast4 KO mice, Co-IP, phosphorylation assay, nuclear localization analysis, gene expression of DLX3 target genes Experimental & molecular medicine High 38945953
2024 METTL3 mediates m6A methylation of pre-miR-665, accelerating its degradation via YTHDF2, thereby reducing miR-665 levels that would otherwise target and suppress DLX3; METTL3 may also directly regulate DLX3 expression via YTHDF1; this METTL3/pre-miR-665/DLX3 pathway controls odonto/osteoblastic differentiation of stem cells from apical papilla. Gain/loss-of-function (METTL3+/- mice), Me-RIP microarray, dual-luciferase reporter assay, rescue experiments, m6A quantification Experimental & molecular medicine Medium 38825638
2018 DLX3 controls the decussation pattern of enamel rods and regulates expression of myosin II complex components potentially involved in driving coordinated ameloblast migration during enamel secretion. Conditional KO in dental epithelium, scanning electron microscopy of enamel rod patterns, expression analysis of myosin II components Connective tissue research Medium 29745813

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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
1999 Placental failure in mice lacking the homeobox gene Dlx3. Proceedings of the National Academy of Sciences of the United States of America 224 9874789
1994 Differential and overlapping expression domains of Dlx-2 and Dlx-3 suggest distinct roles for Distal-less homeobox genes in craniofacial development. Mechanisms of development 217 7893603
1998 Identification of a mutation in DLX3 associated with tricho-dento-osseous (TDO) syndrome. Human molecular genetics 186 9467018
2006 BMP2 commitment to the osteogenic lineage involves activation of Runx2 by DLX3 and a homeodomain transcriptional network. The Journal of biological chemistry 175 17060321
2008 Dlx3 is a crucial regulator of hair follicle differentiation and cycling. Development (Cambridge, England) 113 18684741
1999 Inhibitory patterning of the anterior neural plate in Xenopus by homeodomain factors Dlx3 and Msx1. Developmental biology 100 10433834
2005 DLX3 mutation associated with autosomal dominant amelogenesis imperfecta with taurodontism. American journal of medical genetics. Part A 99 15666299
2000 Regulation and function of Dlx3 in vertebrate development. Developmental dynamics : an official publication of the American Association of Anatomists 76 10906774
1998 A common DLX3 gene mutation is responsible for tricho-dento-osseous syndrome in Virginia and North Carolina families. Journal of medical genetics 66 9783705
2012 Neural crest deletion of Dlx3 leads to major dentin defects through down-regulation of Dspp. The Journal of biological chemistry 63 22351765
2002 Bone morphogenetic protein-2 (BMP-2) transactivates Dlx3 through Smad1 and Smad4: alternative mode for Dlx3 induction in mouse keratinocytes. Nucleic acids research 63 11788714
2001 Distinct roles for Distal-less genes Dlx3 and Dlx5 in regulating ectodermal development in Xenopus. Molecular reproduction and development 62 11599044
2002 Genomic structure and functional control of the Dlx3-7 bigene cluster. Proceedings of the National Academy of Sciences of the United States of America 57 11792834
2005 Expression pattern of Dlx3 during cell differentiation in mineralized tissues. Bone 54 16172034
2008 DLX3 c.561_562delCT mutation causes attenuated phenotype of tricho-dento-osseous syndrome. American journal of medical genetics. Part A 49 18203197
2012 The transcription factor DLX3 regulates the osteogenic differentiation of human dental follicle precursor cells. Stem cells and development 48 22107079
2007 Homeobox gene Dlx3 is regulated by p63 during ectoderm development: relevance in the pathogenesis of ectodermal dysplasias. Development (Cambridge, England) 45 17164413
2011 DLX3 homeodomain mutations cause tricho-dento-osseous syndrome with novel phenotypes. Cells, tissues, organs 43 21252474
2011 Epidermal ablation of Dlx3 is linked to IL-17-associated skin inflammation. Proceedings of the National Academy of Sciences of the United States of America 43 21709238
2014 DLX3 regulates bone mass by targeting genes supporting osteoblast differentiation and mineral homeostasis in vivo. Cell death and differentiation 42 24948010
2009 Homeodomain protein Dlx3 induces phosphorylation-dependent p63 degradation. Cell cycle (Georgetown, Tex.) 40 19282665
2008 Molecular consequences of a frameshifted DLX3 mutant leading to Tricho-Dento-Osseous syndrome. The Journal of biological chemistry 38 18492670
1999 Regulation of the Dlx3 homeobox gene upon differentiation of mouse keratinocytes. The Journal of biological chemistry 38 10473625
2000 The Dlx3 protein harbors basic residues required for nuclear localization, transcriptional activity and binding to Msx1. Journal of cell science 37 11058088
2017 A novel DLX3-PKC integrated signaling network drives keratinocyte differentiation. Cell death and differentiation 36 28186503
2015 Morphological analyses and a novel de novo DLX3 mutation associated with tricho-dento-osseous syndrome in a Chinese family. European journal of oral sciences 33 26104267
2004 Increased bone density associated with DLX3 mutation in the tricho-dento-osseous syndrome. Bone 32 15454107
2014 A protein kinase A (PKA)/β-catenin pathway sustains the BMP2/DLX3-induced osteogenic differentiation in dental follicle cells (DFCs). Cellular signalling 31 25530217
2008 DLX3 mutation in a new family and its phenotypic variations. Journal of dental research 30 18362318
1999 Expression of DLX3 in chick embryos. Mechanisms of development 30 10559497
2007 A 4 bp deletion mutation in DLX3 enhances osteoblastic differentiation and bone formation in vitro. Bone 28 17950683
2019 Mdm2 Promotes Odontoblast-like Differentiation by Ubiquitinating Dlx3 and p53. Journal of dental research 27 31847675
2017 BMP-2 induced Dspp transcription is mediated by Dlx3/Osx signaling pathway in odontoblasts. Scientific reports 27 28883412
2015 The homeoprotein DLX3 and tumor suppressor p53 co-regulate cell cycle progression and squamous tumor growth. Oncogene 27 26522723
2016 The parathyroid hormone-related protein is secreted during the osteogenic differentiation of human dental follicle cells and inhibits the alkaline phosphatase activity and the expression of DLX3. Tissue & cell 26 27368119
2014 BMP-2 induction of Dlx3 expression is mediated by p38/Smad5 signaling pathway in osteoblastic MC3T3-E1 cells. Journal of cellular physiology 26 24647893
2011 Expression and localization of DLX3, PPARG and SP1 in bovine trophoblast during binucleated cell differentiation. Placenta 24 21937107
2018 Novel DLX3 variants in amelogenesis imperfecta with attenuated tricho-dento-osseous syndrome. Oral diseases 23 30095208
2013 In vivo impact of Dlx3 conditional inactivation in neural crest-derived craniofacial bones. Journal of cellular physiology 22 22886599
2000 Regulation of early expression of Dlx3, a Xenopus anti-neural factor, by beta-catenin signaling. Mechanisms of development 22 10704847
2018 miR-675 promotes odontogenic differentiation of human dental pulp cells by epigenetic regulation of DLX3. Experimental cell research 21 29604248
2017 DLX3-Dependent Regulation of Ion Transporters and Carbonic Anhydrases is Crucial for Enamel Mineralization. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 21 27760456
2001 Phosphorylation of murine homeodomain protein Dlx3 by protein kinase C. FEBS letters 21 11343707
2011 Homeobox gene Distal-less 3 (DLX3) is a regulator of villous cytotrophoblast differentiation. Placenta 20 21802725
2008 In vivo impact of a 4 bp deletion mutation in the DLX3 gene on bone development. Developmental biology 20 18996110
2015 Histone demethylase KDM4B regulates otic vesicle invagination via epigenetic control of Dlx3 expression. The Journal of cell biology 19 26598618
2016 Senescence: novel insight into DLX3 mutations leading to enhanced bone formation in Tricho-Dento-Osseous syndrome. Scientific reports 18 27924851
2017 Dlx3 and GCM-1 functionally coordinate the regulation of placental growth factor in human trophoblast-derived cells. Journal of cellular physiology 16 27996093
2017 DLX3 promotes bone marrow mesenchymal stem cell proliferation through H19/miR-675 axis. Clinical science (London, England : 1979) 16 28963438
2012 Hairless plays a role in formation of inner root sheath via regulation of Dlx3 gene. The Journal of biological chemistry 16 22442153
2021 The miR-4739/DLX3 Axis Modulates Bone Marrow-Derived Mesenchymal Stem Cell (BMSC) Osteogenesis Affecting Osteoporosis Progression. Frontiers in endocrinology 15 34925225
2011 SUMOylation of DLX3 by SUMO1 promotes its transcriptional activity. Journal of cellular biochemistry 15 21268066
2007 Down-regulation of DLX3 expression in MLL-AF4 childhood lymphoblastic leukemias is mediated by promoter region hypermethylation. Oncology reports 15 17611665
2022 Dlx3 Ubiquitination by Nuclear Mdm2 Is Essential for Dentinogenesis in Mice. Journal of dental research 14 35220830
2022 Lef1 and Dlx3 May Facilitate the Maturation of Secondary Hair Follicles in the Skin of Gansu Alpine Merino. Genes 14 35893063
2016 DLX3 negatively regulates osteoclastic differentiation through microRNA-124. Experimental cell research 14 26836061
2006 Smad6 represses Dlx3 transcriptional activity through inhibition of DNA binding. The Journal of biological chemistry 14 16687405
2021 Effects of DLX3 on the osteogenic differentiation of induced pluripotent stem cell‑derived mesenchymal stem cells. Molecular medicine reports 12 33655330
2021 Circular RNA hsa_circ_0081343 promotes trophoblast cell migration and invasion and inhibits trophoblast apoptosis by regulating miR-210-5p/DLX3 axis. Reproductive biology and endocrinology : RB&E 12 34365964
2019 DLX3 regulates osteogenic differentiation of bone marrow mesenchymal stem cells via Wnt/β-catenin pathway mediated histone methylation of DKK4. Biochemical and biophysical research communications 12 31202458
2017 DLX3 interacts with GCM1 and inhibits its transactivation-stimulating activity in a homeodomain-dependent manner in human trophoblast-derived cells. Scientific reports 12 28515447
2017 DLX3-Dependent STAT3 Signaling in Keratinocytes Regulates Skin Immune Homeostasis. The Journal of investigative dermatology 12 29246798
2016 Unexpected identification of a recurrent mutation in the DLX3 gene causing amelogenesis imperfecta. Oral diseases 12 26762616
2015 Estrogen Receptor α Regulates Dlx3-Mediated Osteoblast Differentiation. Molecules and cells 12 26674964
2012 Akt1 regulates phosphorylation and osteogenic activity of Dlx3. Biochemical and biophysical research communications 12 22885182
2011 A dominant mutation etiologic for human tricho-dento-osseous syndrome impairs the ability of DLX3 to downregulate ΔNp63α. Journal of cellular physiology 12 21520071
1994 Molecular cloning and evolutional analysis of a mammalian homologue of the Distal-less 3 (Dlx-3) homeobox gene. FEBS letters 12 7915995
2015 Association of DLX3 gene polymorphism and dental caries susceptibility in Japanese children. Archives of oral biology 11 25247779
2014 Protein kinase a phosphorylates Dlx3 and regulates the function of Dlx3 during osteoblast differentiation. Journal of cellular biochemistry 11 24924519
2006 Dlx3 is expressed in the ventral forebrain of chicken embryos: implications for the evolution of the Dlx gene family. The International journal of developmental biology 11 16323080
2019 DLX3 epigenetically regulates odontoblastic differentiation of hDPCs through H19/miR-675 axis. Archives of oral biology 10 31029881
2018 DLX3 Inhibits the Proliferation of Human Dental Pulp Cells Through Inactivation of Canonical Wnt/β-Catenin Signaling Pathway. Frontiers in physiology 10 30524303
2013 Downstream targets of the homeobox gene DLX3 are differentially expressed in the placentae of pregnancies affected by human idiopathic fetal growth restriction. Molecular and cellular endocrinology 10 23831639
2013 Osteogenesis imperfecta, tricho-dento-osseous syndrome and intellectual disability: a familial case with 17q21.33-q22 (COL1A1 and DLX3) deletion and 7q32.3-q33 duplication resulting from a reciprocal interchromosomal insertion. American journal of medical genetics. Part A 10 23949819
2024 METTL3-mediated pre-miR-665/DLX3 m6A methylation facilitates the committed differentiation of stem cells from apical papilla. Experimental & molecular medicine 9 38825638
2019 Do DLX3 and CD271 Protect Human Keratinocytes from Squamous Tumor Development? International journal of molecular sciences 9 31331058
2018 Pleiotropic function of DLX3 in amelogenesis: from regulating pH and keratin expression to controlling enamel rod decussation. Connective tissue research 9 29745813
2009 Thickness and microhardness of deciduous tooth enamel with known DLX3 mutation. Archives of oral biology 9 19608154
2022 Novel DLX3 variant identified in a family with tricho-dento-osseous syndrome. Archives of oral biology 8 35714441
2021 Loss of DLX3 tumor suppressive function promotes progression of SCC through EGFR-ERBB2 pathway. Oncogene 7 33947961
2023 CHIP inhibits odontoblast differentiation through promoting DLX3 polyubiquitylation and degradation. Development (Cambridge, England) 6 37213079
2020 "Isolated" Amelogenesis Imperfecta Associated with DLX3 Mutation: A Clinical Case. Case reports in genetics 6 32832172
2017 Lack of Association between BMP2/DLX3 Gene Polymorphisms and Dental Caries in Primary and Permanent Dentitions. Caries research 6 29059672
2015 Functional Characterization of a Single Nucleotide Polymorphism in the 3' Untranslated Region of Sheep DLX3 Gene. PloS one 6 26332462
2019 Promoter methylation and expression pattern of DLX3, ATF4, and FRA1 genes during osteoblastic differentiation of adipose-derived mesenchymal stem cells. BioImpacts : BI 5 32983940
2017 DLX3 mutation negatively regulates odontogenic differentiation of human dental pulp cells. Archives of oral biology 5 28135572
2016 Transcription factor Dlx3 induces aryl hydrocarbon receptor promoter activity. Biochemistry and biophysics reports 5 27777986
2023 Loss of Bmp2 impairs odontogenesis via dysregulating pAkt/pErk/GCN5/Dlx3/Sp7. Research square 4 37790473
2023 A novel DLX3 mutation causes tricho-dento-osseous syndrome with abnormal enamel structure and formation. Archives of oral biology 4 38006713
2022 Salt Dependence of DNA Binding Activity of Human Transcription Factor Dlx3. International journal of molecular sciences 4 36012753
2012 Theria-specific homeodomain and cis-regulatory element evolution of the Dlx3-4 bigene cluster in 12 different mammalian species. Journal of experimental zoology. Part B, Molecular and developmental evolution 4 22951979
2024 MAST4 regulates stem cell maintenance with DLX3 for epithelial development and amelogenesis. Experimental & molecular medicine 3 38945953
2022 The Imbalance Expression of DLX3 May Perform Critical Function in the Occurrence and Progression of Preeclampsia. Computational and mathematical methods in medicine 3 35096127
2020 ATF4, DLX3, FRA1, MSX2, C/EBP-ζ, and C/EBP-α Shape the Molecular Basis of Therapeutic Effects of Zoledronic Acid in Bone Disorders. Anti-cancer agents in medicinal chemistry 3 32698734
2024 CircFgfr2 promotes osteogenic differentiation of rat dental follicle cells by targeting the miR-133a-3p/DLX3 signaling pathway. Heliyon 2 38912473
2022 miR-9-5p promotes myogenic differentiation via the Dlx3/Myf5 axis. PeerJ 2 35529491
2017 A de novo germline mutation of DLX3 in a Brown Swiss calf with tricho-dento-osseus-like syndrome. Veterinary dermatology 2 28670783
2025 Impact of DLX3/SAHH axis on osteogenic differentiation of BMSCs in alveolar bone. Journal of oral biosciences 1 40180282
2024 Association Between the Risk of Dental Caries and DLX3 Gene Polymorphisms in Chinese Children. Oral health & preventive dentistry 1 39400082