Affinage

DLX3

Homeobox protein DLX-3 · UniProt O60479

Length
287 aa
Mass
31.7 kDa
Annotated
2026-06-09
100 papers in source corpus 44 papers cited in narrative 43 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DLX3 is a homeodomain transcription factor that governs differentiation programs in mineralized tissues, epidermis, and placenta, binding the consensus 5'-TAATT-3' sequence through its α3 helix and L1 loop (PMID:36012753) via a bipartite nuclear localization signal required for nuclear targeting, DNA binding, and transactivation (PMID:11058088). It functions as the effector of a BMP2 signaling axis: BMP2 induces DLX3 transcription through Smad1/Smad4 (PMID:11788714) or p38/Smad5 (PMID:24647893) binding to its promoter, and DLX3 in turn drives osteoblast and odontoblast differentiation by directly activating Runx2 (PMID:17060321), Dspp (PMID:22351765), and Dkk1 (PMID:30524303), physically partnering with Runx2 (PMID:15456894), Sp7/Osx (PMID:28883412), and p53 (PMID:26522723) to co-regulate downstream genes; loss of DLX3 in vivo paradoxically increases bone mass through earlier DLX5/RUNX2 promoter occupancy (PMID:24948010). DLX3 activity is extensively tuned by post-translational modification—PKCα phosphorylation at S138 inhibits DNA binding (PMID:11343707), PKA at S10 (PMID:24924519) and Akt1 (PMID:22885182) increase stability and activity, SUMO1 at K112 enhances transactivation (PMID:21268066), MDM2 monoubiquitination activates it (PMID:31847675) while CHIP K63-polyubiquitination targets it for degradation in direct competition with MDM2 (PMID:37213079), and MAST4 phosphorylates its NLS to drive nuclear translocation (PMID:38945953). In epidermis, DLX3 enforces keratinocyte differentiation and homeostasis: it triggers Raf1-dependent proteasomal degradation of ΔNp63α (PMID:19282665) and interacts with p53 on the p21 promoter to impose G1-S arrest (PMID:26522723), and its epidermal loss provokes STAT3-dependent inflammation (PMID:29246798) and EGFR-ERBB2-driven squamous tumorigenesis (PMID:33947961). In placenta, DLX3 is essential for trophoblast development (PMID:9874789), driving cytotrophoblast differentiation (PMID:21802725) and co-regulating PGF through functional antagonism with GCM1 (PMID:27996093, PMID:28515447). A frameshift mutation in DLX3 causes tricho-dento-osseous syndrome (PMID:9467018), consistent with its requirement across hair, tooth, and bone development.

Mechanistic history

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

    Establishing that DLX3 mutation causes human disease defined its physiological importance across hair, teeth, and bone before its molecular mechanism was known.

    Evidence Genomic cloning and mutational analysis of a 4 bp frameshift deletion in six tricho-dento-osseous syndrome families

    PMID:9467018

    Open questions at the time
    • Mechanism by which the frameshift product disrupts function not resolved here
    • Tissue-specific contributions not separated
  2. 1999 High

    Knockout demonstrated DLX3 is essential for placental trophoblast development, establishing an early non-redundant developmental role.

    Evidence Targeted Dlx3 deletion in mice with in situ hybridization and genetic epistasis on Esx1

    PMID:9874789

    Open questions at the time
    • Direct transcriptional targets in trophoblast not defined
    • Embryonic lethality precludes analysis of later roles
  3. 1999 Medium

    Functional studies in Xenopus and on the Dlx3 promoter began defining its regulatory inputs and its activity as a context-dependent repressor of neural markers.

    Evidence Xenopus overexpression/loss-of-function and keratinocyte promoter dissection (NF-Y/CCAAT, Sp1, Ca2+ elements)

    PMID:10433834 PMID:10473625 PMID:10704847

    Open questions at the time
    • Mammalian relevance of Xenopus neural repression not established
    • Direct neural target genes not identified
  4. 2000 High

    Mapping the bipartite NLS linked nuclear targeting to DNA binding, transactivation, and Msx1 interaction, defining the structural basis of DLX3 nuclear function.

    Evidence NLS mutagenesis, GFP-fusion localization, yeast one-hybrid, and in vitro interaction assays in keratinocytes

    PMID:11058088

    Open questions at the time
    • Msx1 interaction surface not mapped
    • Regulation of nuclear import in vivo not addressed
  5. 2002 High

    Identifying BMP2→Smad1/4 induction of DLX3 placed it as a downstream effector of BMP signaling in epithelial differentiation.

    Evidence Promoter deletion/mutagenesis, gel shift with recombinant Smad1/Smad4, supershift, and luciferase reporter in keratinocytes

    PMID:11788714

    Open questions at the time
    • Whether the same axis operates identically across cell types not tested here
  6. 2006 High

    Defining the DLX3-Runx2 relationship clarified how DLX3 both physically engages and transcriptionally activates the master osteoblast regulator.

    Evidence ChIP, Runx2 interaction mapping (aa 376-432), promoter assays, siRNA, and Runx2-null rescue in osteoprogenitors

    PMID:15456894 PMID:17060321

    Open questions at the time
    • Whether DLX3 represses or activates Runx2-dependent transcription is context-dependent and unresolved
    • Stoichiometry of DLX3/Runx2/Msx2 promoter exchange unknown
  7. 2007 Medium

    Placing DLX3 downstream of p63 connected it to a defined ectodermal developmental transcriptional cascade and to AEC dysplasia.

    Evidence Genetic/transcriptional analysis in mouse with p63 SAM-domain mutation reporter assays

    PMID:17164413

    Open questions at the time
    • Direct p63 binding to Dlx3 regulatory regions not shown
    • Whether regulation is direct or indirect unresolved
  8. 2008 High

    Conditional epidermal knockout and dominant-negative analysis revealed DLX3's requirement in hair follicle differentiation and the molecular consequence of the TDO mutation.

    Evidence K14-Cre conditional KO with Wnt/BMP epistasis, plus EMSA and co-expression assays of the TDO frameshift mutant

    PMID:18492670 PMID:18684741

    Open questions at the time
    • Direct hair-follicle target genes incompletely mapped
    • Mechanism of dominant-negative complex DNA binding not structurally resolved
  9. 2009 Medium

    Demonstrating DLX3-triggered, Raf1-dependent degradation of ΔNp63α established a feedback loop in epidermal differentiation control.

    Evidence Co-expression, proteasome inhibition, Raf1 depletion, and p63 phosphosite mutagenesis

    PMID:19282665

    Open questions at the time
    • E3 ligase mediating ΔNp63α degradation not identified
    • Direct vs indirect role of DLX3 in degradation not separated
  10. 2011 High

    Multiple advances established DLX3's roles in skin inflammation, trophoblast differentiation, Smad6 antagonism, and SUMO regulation, broadening its mechanistic repertoire.

    Evidence K14Cre conditional KO with cytokine profiling; BeWo overexpression differentiation assays; Smad6 IP/domain mapping/EMSA; SUMO1 mutagenesis and reporter assays

    PMID:16687405 PMID:21268066 PMID:21709238 PMID:21802725

    Open questions at the time
    • SUMO E3 ligase for DLX3 not identified
    • Mechanistic link between DLX3 loss and IL-17 axis indirect
  11. 2012 High

    Conditional knockouts and kinase studies tied DLX3 directly to Dspp-driven dentinogenesis and revealed phosphorylation-based stability control by Akt1.

    Evidence Wnt1-Cre conditional KO with ChIP-seq and Dspp reporter; in vitro Akt1 kinase assay with transcriptional readouts; PKA S10 phosphorylation mapping; Hairless promoter regulation

    PMID:22351765 PMID:22442153 PMID:22885182 PMID:24924519

    Open questions at the time
    • Integration of multiple phosphorylation inputs not addressed
    • Akt1 and PKA phosphosite crosstalk unresolved
  12. 2014 High

    Conditional skeletal knockouts with RNA-seq/ChIP-seq revealed that DLX3 loss increases bone mass via altered DLX5/RUNX2 promoter dynamics, refining its role as a tempering regulator of osteogenesis.

    Evidence Prx1-Cre and OCN-Cre conditional KO, micro-CT, dynamic histomorphometry, RNA-seq, ChIP-seq; plus p38/Smad5 promoter induction analysis

    PMID:24647893 PMID:24948010

    Open questions at the time
    • Reconciling DLX3 as both Runx2 activator and bone-mass restrainer not fully mechanistic
    • Direct vs compensatory effects of DLX5/6 not separated
  13. 2015 High

    Discovery of DLX3-p53 cooperation on p21, ER-α regulation, and KDM4B-mediated epigenetic maintenance connected DLX3 to cell-cycle control and to upstream chromatin and hormonal inputs.

    Evidence Reciprocal Co-IP, ChIP, cell-cycle/migration assays (p53/p21); Co-IP and DNA binding assays (ER-α); in vivo ChIP and catalytic-mutant rescue (KDM4B)

    PMID:26522723 PMID:26598618 PMID:26674964

    Open questions at the time
    • DLX3-p53 binding surface not mapped
    • Physiological context of ER-α regulation unclear
  14. 2017 High

    A cluster of studies established DLX3's roles in enamel maturation via ion-transport genes, ameloblast migration, odontoblast Dspp regulation with Osx, PKCα feedback, GCM1 antagonism in placenta, MDM2 monoubiquitination, and STAT3 control in skin.

    Evidence Multiple conditional KOs with ChIP-seq, EMSA, Co-IP, ubiquitination assays, mammalian one-hybrid, and pharmacological rescue across tooth, skin, and trophoblast systems

    PMID:27760456 PMID:27996093 PMID:28186503 PMID:28515447 PMID:28883412 PMID:29246798 PMID:29745813 PMID:31847675

    Open questions at the time
    • How tissue context selects among DLX3 partners not resolved
    • Direct vs network-level effects on STAT3 and EGFR-ERBB2 not fully separated
  15. 2018 Medium

    Identifying DLX3 activation of Dkk1 linked it to suppression of canonical Wnt/β-catenin signaling and proliferation in dental pulp cells.

    Evidence ChIP, reporter assays with DLX3-responsive-element mutagenesis, DKK1 knockdown and LiCl rescue

    PMID:30524303

    Open questions at the time
    • Whether Dkk1 regulation operates in other DLX3 tissues untested
  16. 2019 High

    Characterization of MDM2 monoubiquitination and H3K27me3-dependent DKK4 regulation extended DLX3 control to ubiquitin-based activation and epigenetic modulation of Wnt signaling.

    Evidence Co-IP, proximity ligation assay, ubiquitination and reporter assays (MDM2); ChIP-qPCR for H3K27me3 and differentiation assays (DKK4)

    PMID:31202458 PMID:31847675

    Open questions at the time
    • Mechanism by which monoubiquitination enhances transactivation unknown
    • Direct vs indirect H3K27me3 effect at DKK4 unresolved
  17. 2021 Medium

    Two-stage carcinogenesis revealed DLX3 as a tumor suppressor in skin restraining the EGFR-ERBB2 pathway.

    Evidence Dlx3 conditional KO with DMBA/TPA carcinogenesis and whole transcriptome analysis

    PMID:33947961

    Open questions at the time
    • Direct DLX3 targets restraining EGFR-ERBB2 not identified
    • Whether tumor suppression is cell-autonomous unresolved
  18. 2022 High

    In vivo MDM2 dissection, CHIP-mediated K63 degradation, MAST4 phosphorylation of the NLS, structural definition of the DNA-binding consensus, and myogenic regulation by miR-9-5p completed a detailed picture of DLX3 post-translational and DNA-binding control.

    Evidence Conditional MDM2/Stub1/MAST4 KO mice, in-tissue PLA, domain mutagenesis, K63 ubiquitination assays, NMR of the homeodomain-DNA complex, and C2C12 luciferase/functional assays

    PMID:35220830 PMID:35529491 PMID:36012753 PMID:37213079 PMID:38945953

    Open questions at the time
    • NMR DNA-binding model lacks mutagenesis validation
    • Competitive balance of MDM2 vs CHIP in different tissues not quantified
  19. 2024 Medium

    BMP2-induced phosphorylation of DLX3 promoting a DLX3-Sp7-GCN5 complex on Dspp/Dmp1 promoters refined how kinase signaling assembles an active transcriptional complex for dentinogenesis.

    Evidence ChIP/Re-ChIP, promoter assays, RNA-seq, and Bmp2 conditional KO mice (preprint)

    PMID:37790473

    Open questions at the time
    • Preprint not yet peer reviewed
    • Phosphosites mediating Sp7 interaction not precisely mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse post-translational modifications and tissue-specific partners are integrated to determine DLX3 output in a given cell type remains unresolved.
  • No unified model linking phosphorylation, SUMOylation, and ubiquitination states to specific target gene programs
  • Structural basis of partner selection (Runx2 vs Sp7 vs GCM1 vs p53) not determined
  • Quantitative dynamics of MDM2-activating vs CHIP-degrading ubiquitination in vivo not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 3
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 1
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1643685 Disease 2 R-HSA-392499 Metabolism of proteins 2
Partners
GCM1MAST4MDM2RUNX2SMAD6SP7STUB1TP53

Evidence

Reading pass · 43 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 Dlx3 is required for maintenance of Esx1 expression in placental tissue. Gene targeting (knockout mouse), in situ hybridization, genetic epistasis Proceedings of the National Academy of Sciences of the United States of America High 9874789
1998 A 4 bp deletion in DLX3 (frameshift causing premature stop codon) is causally associated with tricho-dento-osseous syndrome, linking DLX3 to development of hair, teeth, and bone. Genomic cloning, sequencing, mutational analysis in six TDO families Human molecular genetics High 9467018
2000 Dlx3 contains a bipartite nuclear localization signal (NLS) required for nuclear targeting, specific DNA binding, transcriptional activation, and physical interaction with Msx1 protein in vitro. Mutational analysis of NLS, GFP fusion localization in keratinocytes, yeast one-hybrid transcriptional assay, in vitro protein interaction assay Journal of cell science High 11058088
1999 Dlx3 acts as a transcriptional repressor of panneural markers (including Zic family genes and BF-1) in the anterior neural plate of Xenopus, while permitting expression of anterior neural plate genes (Otx2, cement gland markers); this is distinct from Msx1 which inhibits anterior markers. Xenopus overexpression and loss-of-function, in situ hybridization, epistasis Developmental biology Medium 10433834
1999 Dlx3 promoter activity in keratinocytes is driven by NF-Y (CBF) binding to a CCAAT box between -84 and -34, and by an Sp1 binding site upstream of the transcription start site; elements between +30 and +60 mediate Ca2+-dependent induction during differentiation. Serial deletion analysis, gel retardation assays, mutational analysis of Dlx3 promoter in primary keratinocytes The Journal of biological chemistry Medium 10473625
2001 PKCα phosphorylates Dlx3 at serine 138 within the homeodomain, and this phosphorylation partially inhibits Dlx3-DNA complex formation. In vitro kinase assay, keratinocyte nuclear extract kinase reaction with PKC inhibitor, deletion and mutational analysis of Dlx3 FEBS letters High 11343707
2002 BMP-2 induces Dlx3 transcription in keratinocytes via Smad1 and Smad4 binding to a GCAT motif in the Dlx3 promoter (-1917 to -1747 region); mutation of the Smad1/Smad4-binding site abolishes BMP-2-dependent activation. Promoter deletion and mutational analysis, gel shift assays with recombinant Smad1/Smad4, supershift assays with nuclear extracts, luciferase reporter assay Nucleic acids research High 11788714
2004 Dlx3 is recruited to the osteocalcin (OC) gene promoter during postproliferative osteoblast differentiation (replacing Msx2), and physically interacts with Runx2 via Runx2 amino acids 376-432, reducing Runx2-mediated transcription. Chromatin immunoprecipitation (ChIP), protein-protein interaction assay, OC promoter luciferase assay, Runx2 deletion analysis, siRNA knockdown, overexpression in osteoprogenitors Molecular and cellular biology High 15456894
2006 BMP2 induces DLX3, which in turn activates Runx2 gene transcription; siRNA knockdown of DLX3 reduces Runx2 expression; forced DLX3 expression in Runx2-null cells suffices to induce Runx2, osteocalcin, and alkaline phosphatase transcription. MSX2 and CDP/cut repress Runx2, while DLX3 and DLX5 activate it. siRNA knockdown, forced overexpression in Runx2-null cells, promoter mutagenesis, ChIP for HD protein and RNA polymerase II occupancy on Runx2 chromatin The Journal of biological chemistry High 17060321
2007 Dlx3 is a downstream target of p63; transcription of Dlx3 is abrogated by mutations in the SAM domain of p63 (associated with AEC dysplasias) but not by EEC, LMS, or SHFM mutations, placing Dlx3 in a p63-dependent transcriptional cascade for ectoderm development. Genetic and transcriptional analysis in mouse, reporter assays, p63 mutation analysis Development (Cambridge, England) Medium 17164413
2008 The TDO-associated DLX3 frameshift mutant (DLX3(TDO)) cannot bind to canonical Dlx3 binding sites; when co-expressed with wild-type DLX3, they form a complex capable of DNA binding, but DLX3(TDO) exerts a dominant-negative effect on DLX3(WT) transcriptional activity. Electrophoresis mobility shift assay (EMSA), immunocytochemical analysis, tetracycline-inducible cell lines, co-expression transcriptional assays The Journal of biological chemistry High 18492670
2008 Epidermal-specific ablation of Dlx3 results in complete alopecia due to failure of hair shaft and inner root sheath formation, abnormal cortex differentiation; Dlx3 is positioned downstream of Wnt signaling and upstream of Hoxc13 and Gata3 in the hair follicle differentiation cascade; loss of Dlx3 in telogen bulge stem cells abolishes BMP signaling and prevents hair cycle re-initiation. Conditional knockout (K14-Cre), histology, gene expression analysis, epistasis with Wnt and BMP signaling pathways, co-localization of phospho-Smad1/5/8 and Dlx3 Development (Cambridge, England) High 18684741
2009 DLX3 triggers proteasome-dependent degradation of ΔNp63α via a pathway requiring Raf1 phosphorylation; Thr397 and Ser383 of ΔNp63α are required for Dlx3-mediated degradation; Dlx3 cannot promote p63 degradation in Raf1-depleted cells or upon pharmacological Raf1 knockdown. Transient expression/co-expression assays, proteasome inhibitor treatment, Raf1 depletion (siRNA and pharmacological), site-directed mutagenesis of p63 phosphorylation sites Cell cycle (Georgetown, Tex.) Medium 19282665
2011 Epidermal ablation of Dlx3 results in epidermal hyperproliferation, abnormal keratinocyte differentiation, and IL-17-associated cutaneous inflammation with accumulation of IL-17-producing T cells; the gene expression signature overlaps with psoriatic skin. Conditional knockout mouse model (K14Cre), histology, immunophenotyping, cytokine profiling Proceedings of the National Academy of Sciences of the United States of America High 21709238
2011 DLX3 can be SUMOylated by SUMO1 at K112 (not K83) in its N-terminal domain; SUMOylation does not prevent nuclear localization or DNA binding but positively regulates DLX3 transcriptional activity as shown by reduced activity of K112R mutant. Co-expression SUMOylation assay, site-directed mutagenesis (K83R, K112R), immunocytochemical analysis, EMSA, luciferase reporter assay Journal of cellular biochemistry High 21268066
2011 Dlx3 and Smad6 physically interact in human choriocarcinoma cells and differentiated trophoblasts; the Smad6 interaction domain in Dlx3 maps to residues 80-163 (overlapping with homeodomain); Smad6 inhibits Dlx3 binding to at least one Dlx3 binding site in the Esx1 promoter and reduces Dlx3-dependent Esx1 transcription; Dlx4 also binds Smad6 in the same region. Immunocytochemistry, immunoprecipitation, in vitro protein interaction mapping, EMSA, luciferase reporter assay, siRNA knockdown The Journal of biological chemistry High 16687405
2012 Neural crest-specific deletion of Dlx3 causes major dentin defects with hypoplastic dentin and enlarged pulp chambers; Dlx3 directly binds the Dspp promoter in vivo and positively regulates Dspp expression, establishing a regulatory pathway from Dlx3 to dentin matrix formation. Conditional knockout (Wnt1-Cre neural crest), histology, ChIP-seq, luciferase reporter assay The Journal of biological chemistry High 22351765
2012 Akt1 phosphorylates Dlx3 and increases its protein stability, osteogenic transcriptional activity, and DNA binding; BMP2 increases Dlx3 protein levels in an Akt1 activity-dependent manner; inhibition of Akt1 decreases Dlx3 protein levels. In vitro kinase assay, Akt1 overexpression/inhibition, luciferase reporter assay, western blotting Biochemical and biophysical research communications Medium 22885182
2012 Hairless (HR) protein down-regulates Dlx3 mRNA expression through suppression of Dlx3 promoter activity; Dlx3 in turn regulates IRS keratin expression; loss of HR leads to suppressed Dlx3 expression and abnormal inner root sheath formation. Hr mutant mouse model, promoter activity assay, gene expression analysis The Journal of biological chemistry Medium 22442153
2014 In vivo conditional loss of DLX3 in mesenchymal cells or osteoblasts leads to increased bone mass accrual with increased osteoblast activity; RNA-seq and ChIP-seq show DLX3 directly regulates bone formation genes (Dlx5, Dlx6, Runx2, Sp7, Ibsp, Enpp1, Mepe, Opg); without DLX3, DLX5 and RUNX2 show increased and earlier occupancy on the osteocalcin promoter. Conditional knockout (Prx1-Cre, OCN-Cre), dynamic bone formation analysis, histology, micro-CT, RNA-seq, ChIP-seq, Q-PCR Cell death and differentiation High 24948010
2014 PKA phosphorylates Dlx3 at serine 10; this phosphorylation increases BMP2-induced Dlx3 protein stability, DNA binding, and transcriptional activity; substitution of serine 10 to alanine significantly reduces PKA-mediated phosphorylation and abolishes PKA regulation of Dlx3 function. In vitro kinase assay, site-directed mutagenesis (S10A), luciferase reporter assay, PKA activation/inhibition, western blotting Journal of cellular biochemistry Medium 24924519
2015 DLX3 and p53 physically interact on the p21 promoter and co-regulate p21 expression; DLX3 elevation produces a G1-S blockade with p53 transcriptional signatures; loss of DLX3 promotes ERK activation; DLX3 re-expression attenuates SCC cell migration. Co-immunoprecipitation, chromatin immunoprecipitation, transcriptomic analysis, loss/gain of function, cell cycle analysis Oncogene High 26522723
2015 Estrogen receptor α (ER-α) is a positive regulator of Dlx3 transcription; ER-α physically interacts with Dlx3 and increases its transcriptional activity and DNA binding affinity; this regulation is independent of the estradiol ligand-binding domain. Co-immunoprecipitation, luciferase reporter assay, DNA binding affinity assay, domain deletion analysis Molecules and cells Medium 26674964
2015 KDM4B histone demethylase directly occupies the Dlx3 locus regulatory regions in vivo, demethylating H3K9me3 to maintain Dlx3 expression; KDM4B knockdown reduces Dlx3 expression; DLX3 or KDM4B construct co-electroporation rescues ear invagination defects caused by KDM4B knockdown; catalytically dead KDM4B does not rescue. ChIP in vivo, knockdown experiments, rescue co-electroporation with catalytic mutant control, phenotypic analysis of otic vesicle development The Journal of cell biology High 26598618
2017 DLX3 and GCM1 co-occupy a regulatory element on the PGF promoter and coordinate PGF expression in human trophoblast cells; individually both are positive regulators, but co-overexpression causes antagonism; DLX3 physically interacts with GCM1 via its homeodomain, inhibiting GCM1 transactivation activity in a homeodomain-dependent manner; the DLX3 TDO mutant retains this inhibitory activity. Overexpression/knockdown, luciferase reporter with site-directed mutagenesis, ChIP, immunoprecipitation, mammalian one-hybrid assay Scientific reports / Journal of cellular physiology High 27996093 28515447
2017 DLX3 expression and its downstream keratinocyte differentiation signaling depend on PKCα activity; PKCα activation upregulates DLX3; DLX3 loss enhances PKCα activation suggesting feedback; ChIP-seq of suprabasal keratinocytes shows DLX3 binding to proximal promoters of cell cycle, structural, and transcription factor genes. K5-PKCα transgenic mice, DLX3cKO mice, TPA treatment, PKC inhibitor treatment, ChIP-seq Cell death and differentiation High 28186503
2017 DLX3 regulates Dspp transcription in odontoblasts through Dlx3/Osx pathway: BMP-2 induces nuclear translocation of both Dlx3 and Osx; Osx is a downstream target of Dlx3; both Dlx3 and Osx bind the Dspp promoter at specific sites confirmed by EMSA, ChIP, and mutagenesis; Dlx3 and Osx physically interact by co-immunoprecipitation. Luciferase reporter assay, EMSA, ChIP, site-directed mutagenesis, co-immunoprecipitation, in vitro/in vivo expression analysis Scientific reports High 28883412
2017 DLX3 ablation in epidermis results in activated STAT3 signaling; topical STAT3 inhibitor attenuates the immune phenotype of DLX3-null skin; DLX3 is identified as a critical regulator of STAT3 signaling network for skin homeostasis. Tamoxifen-inducible conditional knockout (K14CreERT;DLX3fl/fl), transcriptome profiling, RNA-seq, topical STAT3 inhibitor treatment The Journal of investigative dermatology High 29246798
2017 Conditional dental epithelium-specific Dlx3 knockout results in chalky hypomineralized enamel; DLX3 regulates expression of ion transporters and carbonic anhydrases (not enamel matrix proteins) via direct promoter binding demonstrated by ChIP-seq, and this disrupts characteristic pH oscillations required for enamel maturation. Conditional knockout, transcriptomic analysis, ChIP-seq on rat enamel organ, pH staining Journal of bone and mineral research High 27760456
2018 DLX3 directly binds to the Dkk1 promoter (region -1656 to -1245) at two DLX3 responsive elements and stimulates Dkk1 expression, thereby inhibiting canonical Wnt/β-catenin signaling and reducing proliferation of human dental pulp cells. Luciferase reporter assay, ChIP assay, mutagenesis of DLX3 responsive elements, DKK1 knockdown rescue, lithium chloride treatment rescue Frontiers in physiology Medium 30524303
2018 DLX3 controls coordinated ameloblast migration and enamel rod decussation pattern, and regulates expression of myosin II complex components potentially involved in ameloblast movement. Conditional dental epithelium Dlx3 knockout, histological analysis of enamel rod decussation, gene expression analysis Connective tissue research Medium 29745813
2019 MDM2 E3 ubiquitin ligase physically interacts with Dlx3 in the nucleus (demonstrated by co-immunoprecipitation and in situ proximity ligation assay), monoubiquitinates Dlx3, and this monoubiquitination enhances Dlx3 transcriptional activity on the Dspp promoter and promotes odontoblast differentiation. Co-immunoprecipitation, immunofluorescence co-localization, proximity ligation assay, ubiquitination assay, luciferase reporter assay, siRNA knockdown Journal of dental research High 31847675
2019 DLX3 promotes osteogenic differentiation of BMSCs via Wnt/β-catenin pathway by decreasing H3K27me3 enrichment at the DKK4 promoter, thereby modulating DKK4 expression; ChIP-qPCR confirmed epigenetic regulation. Lentiviral overexpression/knockdown, ChIP-qPCR for H3K27me3, RT-qPCR, western blotting, alizarin red staining Biochemical and biophysical research communications Medium 31202458
2021 Loss of DLX3 in skin epithelium leads to spontaneous activation of the EGFR-ERBB2 pathway; DLX3cKO mice develop more tumors more rapidly in DMBA/TPA two-stage carcinogenesis; transcriptome analysis identifies EGFR-ERBB2 as the pathway activated by Dlx3 loss. Conditional knockout (Dlx3cKO), DMBA/TPA two-stage carcinogenesis, whole transcriptome analysis Oncogene Medium 33947961
2022 Nuclear MDM2 ubiquitinates Dlx3 in odontoblasts in vivo (confirmed by proximity ligation assay); Dlx3 promotes MDM2 nuclear translocation; Dlx3 interacts with MDM2 via its C-terminal domain; deletion of this domain reverses MDM2-mediated enhancement of odontoblast differentiation and Dspp promoter activation; in vivo, MDM2 conditional deletion in odontoblasts impairs dentinogenesis in a p53-independent manner. Conditional knockout (Dmp1-Cre;Mdm2), proximity ligation assay in vivo, domain deletion mutagenesis, Nutlin-3a treatment (p53-MDM2 axis inhibition), luciferase reporter assay Journal of dental research High 35220830
2022 MAST4 kinase directly binds DLX3 and phosphorylates it at three residues within the nuclear localization site, promoting DLX3 nuclear translocation; MAST4-mediated phosphorylation of DLX3 controls transcription of carbonic anhydrase and ion transporter target genes involved in pH regulation during ameloblast maturation. MAST4 knockout mice, co-immunoprecipitation/direct binding assay, phosphorylation mapping, nuclear translocation assay, gene expression analysis Experimental & molecular medicine Medium 38945953
2022 DLX3 homeodomain (HD) selectively binds the consensus DNA sequence 5'-TAATT-3' through its α3 helix and L1 loop regions; DNA binding dynamics are salt-concentration dependent; this structural feature may be relevant to TDO syndrome pathogenesis. NMR chemical shift perturbation (Dlx3-HD with 10-bp DNA duplex under varying salt conditions), imino proton spectroscopy International journal of molecular sciences Medium 36012753
2023 CHIP E3 ubiquitin ligase interacts with DLX3 and induces K63-linked polyubiquitylation leading to its proteasomal degradation; CHIP knockdown enhances odontoblast differentiation while overexpression inhibits it; CHIP competes with MDM2 for DLX3 modification—MDM2 monoubiquitinates (activates) DLX3 while CHIP K63-polyubiquitinates (degrades) it. Co-immunoprecipitation, ubiquitination assay (K63 linkage), siRNA/overexpression, conditional knockout (Stub1 KO mice), luciferase reporter assay, histological analysis Development (Cambridge, England) High 37213079
2022 miR-9-5p promotes myogenic differentiation by downregulating Dlx3 (binding to its 3'UTR), and Dlx3 in turn suppresses Myf5 expression by binding to the Myf5 promoter, thereby inhibiting myogenic differentiation; Dlx3 overexpression inhibits myotube formation. Luciferase assay for miR-9-5p/Dlx3 3'UTR interaction and Dlx3/Myf5 promoter, overexpression/knockdown in C2C12 cells, western blot, qPCR PeerJ Medium 35529491
2024 BMP2-induced phosphorylation of Dlx3 (at Thr and Tyr residues via Akt and Erk42/44 kinases) facilitates Dlx3 nuclear translocation and promotes Dlx3-Sp7 protein interaction; the Dlx3/Sp7 complex, together with histone acetyltransferase GCN5, occupies Dspp and Dmp1 promoters to activate their transcription. ChIP, Re-ChIP, promoter activity assay, immunohistochemistry, RNA-seq, Bmp2 conditional KO mice Research square (preprint)preprint Medium 37790473
2000 Early expression of Dlx3 in ventral ectoderm of pre-gastrula Xenopus embryos is restricted by β-catenin signaling (but not through Xnr3 or chordin induction); β-catenin represses Dlx3 in dorsal ectoderm, providing a pro-neural bias. β-catenin manipulation in Xenopus, in situ hybridization, epistasis analysis Mechanisms of development Medium 10704847
2011 DLX3 acts upstream of syncytin, 3βHSD, and βhCG in villous cytotrophoblast differentiation; overexpression of DLX3 in BeWo cells increases syncytin and 3βHSD mRNA and β-hCG secretion. DLX3 overexpression construct in BeWo trophoblast cells, forskolin stimulation, mRNA/protein analysis, β-hCG secretion assay Placenta Medium 21802725
2014 BMP-2 induces Dlx3 transcription in osteoblasts via p38/Smad5 signaling; p38 activation is necessary for BMP-2-induced Smad5 phosphorylation and nuclear translocation; two Smad5 binding sites (TGTCT boxes) in the Dlx3 promoter (-698 to -368) are required for p38/Smad5-mediated activation. siRNA knockdown of Smad5/p38, EMSA, ChIP, promoter deletion/mutagenesis, luciferase reporter assay Journal of cellular physiology Medium 24647893

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 230 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 176 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) 46 17164413
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 44 21709238
2011 DLX3 homeodomain mutations cause tricho-dento-osseous syndrome with novel phenotypes. Cells, tissues, organs 43 21252474
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.) 41 19282665
2008 Molecular consequences of a frameshifted DLX3 mutant leading to Tricho-Dento-Osseous syndrome. The Journal of biological chemistry 38 18492670
2000 The Dlx3 protein harbors basic residues required for nuclear localization, transcriptional activity and binding to Msx1. Journal of cell science 38 11058088
1999 Regulation of the Dlx3 homeobox gene upon differentiation of mouse keratinocytes. The Journal of biological chemistry 38 10473625
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
2019 Mdm2 Promotes Odontoblast-like Differentiation by Ubiquitinating Dlx3 and p53. Journal of dental research 28 31847675
2007 A 4 bp deletion mutation in DLX3 enhances osteoblastic differentiation and bone formation in vitro. Bone 28 17950683
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
2022 Lef1 and Dlx3 May Facilitate the Maturation of Secondary Hair Follicles in the Skin of Gansu Alpine Merino. Genes 15 35893063
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
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
2024 METTL3-mediated pre-miR-665/DLX3 m6A methylation facilitates the committed differentiation of stem cells from apical papilla. Experimental & molecular medicine 12 38825638
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 Pleiotropic function of DLX3 in amelogenesis: from regulating pH and keratin expression to controlling enamel rod decussation. Connective tissue research 10 29745813
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
2019 Do DLX3 and CD271 Protect Human Keratinocytes from Squamous Tumor Development? International journal of molecular sciences 9 31331058
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
2015 Functional Characterization of a Single Nucleotide Polymorphism in the 3' Untranslated Region of Sheep DLX3 Gene. PloS one 7 26332462
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
2019 Promoter methylation and expression pattern of DLX3, ATF4, and FRA1 genes during osteoblastic differentiation of adipose-derived mesenchymal stem cells. BioImpacts : BI 6 32983940
2017 Lack of Association between BMP2/DLX3 Gene Polymorphisms and Dental Caries in Primary and Permanent Dentitions. Caries research 6 29059672
2023 A novel DLX3 mutation causes tricho-dento-osseous syndrome with abnormal enamel structure and formation. Archives of oral biology 5 38006713
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
2022 Salt Dependence of DNA Binding Activity of Human Transcription Factor Dlx3. International journal of molecular sciences 4 36012753
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 4 32698734
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
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

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