Affinage

DMRT3

Doublesex- and mab-3-related transcription factor 3 · UniProt Q9NQL9

Length
472 aa
Mass
51.2 kDa
Annotated
2026-04-28
33 papers in source corpus 11 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DMRT3 is a DM-domain transcription factor that specifies inhibitory spinal interneuron identity and orchestrates locomotor circuit function, while also patterning the developing telencephalon. In the spinal cord, DMRT3 is expressed in dI6 interneurons that are rhythmically active during locomotion, receive monosynaptic proprioceptive and supraspinal inputs, and regulate central pattern generator (CPG) neuron activity; loss of DMRT3 in mice disrupts locomotor coordination, and a naturally occurring truncating mutation in horses permits alternate gaits (PMID:22932389, PMID:30578339, PMID:36214727). In the dorsal telencephalon, DMRT3 cooperates with DMRT5 and EMX2 to repress the ventral determinant Gsx2 by binding its enhancer, thereby maintaining cortical dorsoventral identity and regulating hippocampal and neocortical area patterning (PMID:30143575, PMID:28031177). Outside neural contexts, DMRT3 acts as a direct transcriptional activator of targets such as SLC7A11 and OIP5-AS1, and interacts with the OAS3–RNase L complex to promote ESR1 mRNA degradation, with a K272T missense mutation linked to disorders of sex development (PMID:38744789, PMID:32553473).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2008 Medium

    Establishing that DMRT3 is a nuclear DNA-binding transcription factor resolved its basic molecular identity and placed it in the DM-domain family alongside DSX and MAB-3.

    Evidence NLS functional assay and EMSA with zebrafish Dmrt3 DM-domain polypeptide

    PMID:18282142

    Open questions at the time
    • Binding specificity tested with zebrafish ortholog only; mammalian DNA-binding targets not identified
    • No genome-wide target identification or in vivo ChIP at this stage
  2. 2012 High

    Demonstrating that DMRT3 specifies dI6 spinal interneurons and that its loss disrupts locomotor coordination — and that a truncating mutation in horses permits alternate gaits — established DMRT3 as a master regulator of spinal locomotor circuit assembly.

    Evidence Dmrt3-null mice (locomotor and spinal cord analysis) combined with genetic association of DMRT3 Ser301STOP with gait phenotype in horses

    PMID:22932389

    Open questions at the time
    • Direct transcriptional targets in dI6 neurons unknown
    • Electrophysiological properties of Dmrt3-derived neurons not yet characterized
    • Mechanism by which truncated DMRT3 permits alternate gaits rather than simply abolishing function was unresolved
  3. 2017 Medium

    Ruling out that combined loss of DMRT1 and DMRT3 causes 46,XY gonadal dysgenesis narrowed the genetic model for 9p24.3 deletion phenotypes and clarified that DMRT3 is not a major gonadal sex-determination gene in mice.

    Evidence CRISPR/Cas9 Dmrt1;Dmrt3 double knockout mice with gonadal histology

    PMID:28956011

    Open questions at the time
    • Other genes in the 9p24.3 region not tested
    • Potential species-specific differences between mouse and human gonadal roles of DMRT3 not addressed
  4. 2018 High

    Showing that DMRT3 cooperates with DMRT5 and EMX2 to directly repress the Gsx2 enhancer revealed a second major developmental role for DMRT3 in maintaining cortical dorsoventral identity, and that DMRT5 regulates Dmrt3 expression established a cross-regulatory hierarchy.

    Evidence Dmrt3;Dmrt5 double KO mice, DMRT5 conditional overexpression, ChIP on Gsx2 enhancer, cortical patterning analysis

    PMID:28031177 PMID:30143575

    Open questions at the time
    • Full set of cortical enhancers bound by DMRT3 unknown
    • Relative contributions of DMRT3 vs. DMRT5 at shared targets not quantified
  5. 2018 High

    Electrophysiological and circuit-level characterization of Dmrt3-Cre neurons showed they are inhibitory, rhythmically active during fictive locomotion, and directly modulate CPG neuron activity, establishing their functional role within the locomotor circuit.

    Evidence Transgenic Dmrt3-Cre mice, whole-cell patch-clamp, retrograde tracing, molecular subtype characterization

    PMID:30578339

    Open questions at the time
    • Specific synaptic targets of Dmrt3 neurons within the CPG not fully mapped
    • Whether Dmrt3 protein is required in adult neurons for circuit maintenance or only during development unclear
  6. 2020 Medium

    Discovery that DMRT3 interacts with OAS3 to degrade ESR1 mRNA via the OAS3–RNase L pathway, and that a K272T mutation disrupts this interaction, revealed an unexpected non-transcriptional mechanism and linked DMRT3 to disorders of sex development.

    Evidence Co-immunoprecipitation of DMRT3–OAS3–RNase L complex, mRNA stability assays, patient exome sequencing and testis tissue validation

    PMID:32553473

    Open questions at the time
    • Mechanism by which a transcription factor participates in cytoplasmic mRNA degradation not structurally explained
    • Single cohort of patients; independent replication in additional DSD cohorts lacking
    • Reciprocal Co-IP and endogenous complex stoichiometry not established
  7. 2021 Medium

    Single-cell transcriptomics revealed molecularly distinct subtypes among Dmrt3-lineage spinal neurons conserved across zebrafish and mice, providing the molecular basis for functional subfunctionalization within the dI6 domain.

    Evidence scRNA-seq of Dmrt3-lineage neurons from zebrafish and mouse spinal cord with cluster analysis

    PMID:35002627

    Open questions at the time
    • Functional validation linking molecular subtypes to distinct locomotor roles not performed
    • Whether DMRT3 directly regulates the subtype-defining gene programs unknown
  8. 2022 Medium

    Mapping monosynaptic inputs to Dmrt3 neurons from proprioceptive afferents, spinal interneurons, and supraspinal motor centers positioned them as sensory-motor integrators bridging peripheral feedback and descending commands.

    Evidence Monosynaptic retrograde rabies tracing in Dmrt3-Cre mice with immunofluorescence subtype identification

    PMID:36214727

    Open questions at the time
    • Output connectivity of Dmrt3 neurons to specific motor neuron pools not mapped at single-synapse resolution
    • Functional significance of individual input sources not tested by selective silencing
  9. 2024 Medium

    ChIP and reporter assays showed DMRT3 directly activates the SLC7A11 promoter and the lncRNA OIP5-AS1 promoter, extending its characterized direct transcriptional targets beyond neural development to ferroptosis regulation and pyroptosis pathways.

    Evidence ChIP and dual-luciferase assays in NSCLC and bronchial epithelial cell lines, xenograft models, RNA immunoprecipitation

    PMID:38744789 PMID:39287912

    Open questions at the time
    • Physiological relevance of DMRT3-driven SLC7A11 and OIP5-AS1 regulation outside cancer/asthma cell lines unclear
    • Whether DMRT3 activator function in these contexts reflects its in vivo neural role or an ectopic activity not determined
    • Genome-wide binding profile of DMRT3 in any tissue still lacking

Open questions

Synthesis pass · forward-looking unresolved questions
  • A genome-wide map of DMRT3 binding sites in spinal and cortical progenitors, and the structural basis for how DMRT3 selectively activates versus represses target genes, remain unresolved.
  • No ChIP-seq or CUT&RUN in neural tissues
  • Structural basis for transcriptional activation vs. repression not determined
  • Whether adult Dmrt3 protein is required for circuit maintenance is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 4 GO:0140110 transcription regulator activity 3
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-1266738 Developmental Biology 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
DMRT5EMX2OAS3RNASEL

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 DMRT3 is expressed in the dI6 subdivision of spinal cord interneurons and is critical for neuronal specification within this subdivision; Dmrt3-null mice display impaired locomotor activity with abnormal spinal circuit function, positioning DMRT3 as essential for configuring the spinal locomotor network controlling limb movements and stride coordination. Dmrt3-null mouse analysis (loss-of-function), expression profiling of spinal cord interneuron subdivisions, locomotor behavioral assays Nature High 22932389
2012 A premature stop codon (Ser301STOP, C>A) in DMRT3 is permissive for the ability to perform alternate gaits (ambling, pacing) in horses, demonstrating that DMRT3 protein truncation alters locomotor pattern generation. Genetic association of DMRT3 nonsense mutation with gait phenotype in horses; functional validation in Dmrt3-null mice Nature High 22932389
2008 Zebrafish Dmrt3 contains a functional nuclear localization signal (K41GHKR45) within the DM domain that directs nuclear import, and the DM domain polypeptide binds DNA at sites similar to targets of DSX and MAB-3, identifying DMRT3 as a nuclear DNA-binding transcription factor. NLS functional assay (nuclear localization), EMSA (electrophoretic mobility-shift assay) with DM domain polypeptide Biology of the cell Medium 18282142
2018 Inhibitory Dmrt3-Cre spinal interneurons receive extensive synaptic inputs, innervate surrounding CPG neurons, intrinsically regulate CPG neuron electrical activity, and are rhythmically active during fictive locomotion, bursting at frequencies independent of ventral root output, demonstrating direct participation of Dmrt3-derived neurons in locomotor circuit coordination. Transgenic Dmrt3-Cre mice, retrograde tracing, electrophysiology (whole-cell patch-clamp), molecular characterization of interneuron subtypes The Journal of neuroscience High 30578339
2018 DMRT3 and DMRT5 cooperatively repress the ventral telencephalic regulator Gsx2 by binding to a ventral telencephalon-specific enhancer in the Gsx2 locus, thereby maintaining cortical dorsoventral identity in dorsal telencephalic progenitors; this function is shared with the homeobox transcription factor EMX2. Dmrt3;Dmrt5 double knockout mice, Dmrt5 conditional overexpression, ChIP showing DMRT3/DMRT5/EMX2 binding to Gsx2 enhancer, gene expression analysis The Journal of neuroscience High 30143575
2018 DMRT3, together with DMRT5, directly controls hippocampus development and neocortical area map formation; DMRT5 upregulates Dmrt3 expression and negatively regulates its own expression, suggesting a feedback mechanism that stabilizes DMRT5 levels in cortical patterning. Dmrt3 and Dmrt5 single and conditional knockout mice, gene expression analysis, bidirectional gain/loss-of-function models Cerebral cortex Medium 28031177
2020 DMRT3 interacts with OAS3 to promote degradation of ESR1 mRNA via the OAS3-RNase L complex; a missense mutation (K272T) in DMRT3 reduces binding of the DMRT3-OAS3 complex to ESR1 mRNA and RNase L, preventing ESR1 mRNA degradation and leading to increased ESR1 expression and disorders of sex development. Exome sequencing, in vitro protein and RNA analyses, co-immunoprecipitation of DMRT3-OAS3-RNase L complex, mRNA stability assays, patient testis validation Fertility and sterility Medium 32553473
2022 Adult spinal Dmrt3 neurons receive monosynaptic inputs from proprioceptive primary sensory neurons (type Ia2, Ia3, Ib), intrasegmental and intersegmental interneurons (including V2a interneurons and Renshaw cells), and brain motor areas (red nucleus, primary sensorimotor cortex, pontine nuclei), positioning them as sensory-motor integrators in spinal reflex and locomotor circuits. Monosynaptic retrograde replication-deficient rabies virus tracing in Dmrt3-Cre mice, immunofluorescence for interneuron subtype markers The Journal of comparative neurology Medium 36214727
2024 DMRT3 functions as a transcriptional activator of the SLC7A11 promoter in NSCLC cells, with binding to the SLC7A11 promoter region verified by ChIP and dual-luciferase reporter assay; upregulation of DMRT3 increases SLC7A11 transcription and suppresses ferroptosis. ChIP, dual-luciferase reporter assay, western blot, xenograft tumor model, siRNA knockdown in LK-2 and H1650 cells Molecular biotechnology Medium 38744789
2024 DMRT3 transcriptionally upregulates the lncRNA OIP5-AS1 in bronchial epithelial cells, as demonstrated by ChIP and dual-luciferase assay; OIP5-AS1 in turn promotes YAP mRNA stability through binding EIF4A3, linking DMRT3 to the EIF4A3/YAP axis and pyroptosis in asthma. ChIP, dual-luciferase reporter assay, RNA immunoprecipitation, co-immunoprecipitation, RNA pull-down, FISH Immunologic research Medium 39287912
2021 Single-cell transcriptomic analysis of Dmrt3-lineage spinal neurons in zebrafish and mice identified molecularly distinct subtypes within the dI6 domain, characterized by differences in birth order, axon guidance gene expression, neurotransmitter identity, and electrophysiological gene profiles, revealing the molecular basis for subfunctionalization of Dmrt3 interneurons. Single-cell RNA sequencing of Dmrt3-lineage neurons from zebrafish and mouse spinal cord, cluster analysis Frontiers in cellular neuroscience Medium 35002627
2017 CRISPR/Cas9-mediated double knockout of Dmrt1 and Dmrt3 in mice does not recapitulate the 46,XY gonadal dysgenesis observed in 9p24.3 deletion patients, demonstrating that simultaneous loss of DMRT3 and DMRT1 is insufficient to explain the human gonadal phenotype. CRISPR/Cas9 double knockout of Dmrt1 and Dmrt3 in mice, gonadal histology at embryonic and neonatal stages Biochemistry and biophysics reports Medium 28956011

Source papers

Stage 0 corpus · 33 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Mutations in DMRT3 affect locomotion in horses and spinal circuit function in mice. Nature 277 22932389
2014 Worldwide frequency distribution of the 'Gait keeper' mutation in the DMRT3 gene. Animal genetics 53 24444049
2018 Characterization of Dmrt3-Derived Neurons Suggest a Role within Locomotor Circuits. The Journal of neuroscience : the official journal of the Society for Neuroscience 36 30578339
2008 Nuclear localization, DNA binding and restricted expression in neural and germ cells of zebrafish Dmrt3. Biology of the cell 31 18282142
2018 DMRT5, DMRT3, and EMX2 Cooperatively Repress Gsx2 at the Pallium-Subpallium Boundary to Maintain Cortical Identity in Dorsal Telencephalic Progenitors. The Journal of neuroscience : the official journal of the Society for Neuroscience 30 30143575
2010 Frequent silence of chromosome 9p, homozygous DOCK8, DMRT1 and DMRT3 deletion at 9p24.3 in squamous cell carcinoma of the lung. International journal of oncology 27 20596660
2018 DMRT5 Together with DMRT3 Directly Controls Hippocampus Development and Neocortical Area Map Formation. Cerebral cortex (New York, N.Y. : 1991) 25 28031177
2014 The effect of the 'Gait keeper' mutation in the DMRT3 gene on gaiting ability in Icelandic horses. Journal of animal breeding and genetics = Zeitschrift fur Tierzuchtung und Zuchtungsbiologie 25 25073639
2014 The DMRT3 'Gait keeper' mutation affects performance of Nordic and Standardbred trotters. Journal of animal science 23 25085403
2002 Restricted expression of DMRT3 in chicken and mouse embryos. Mechanisms of development 22 14516663
2015 DMRT3 is associated with gait type in Mangalarga Marchador horses, but does not control gait ability. Animal genetics 18 25690906
2015 Different DMRT3 Genotypes Are Best Adapted for Harness Racing and Riding in Finnhorses. The Journal of heredity 17 26285915
2002 Restricted expression of DMRT3 in chicken and mouse embryos. Gene expression patterns : GEP 17 12617839
2018 Selection on the Colombian paso horse's gaits has produced kinematic differences partly explained by the DMRT3 gene. PloS one 15 30118522
2017 CRISPR/Cas9-mediated simultaneous knockout of Dmrt1 and Dmrt3 does not recapitulate the 46,XY gonadal dysgenesis observed in 9p24.3 deletion patients. Biochemistry and biophysics reports 15 28956011
2015 Does heterozygosity at the DMRT3 gene make French trotters better racers? Genetics, selection, evolution : GSE 14 25886871
2021 Single Cell Transcriptomic Analysis of Spinal Dmrt3 Neurons in Zebrafish and Mouse Identifies Distinct Subtypes and Reveal Novel Subpopulations Within the dI6 Domain. Frontiers in cellular neuroscience 12 35002627
2017 To pace or not to pace: a pilot study of four- and five-gaited Icelandic horses homozygous for the DMRT3 'Gait Keeper' mutation. Animal genetics 11 29023800
2020 Genetic analysis of a Taiwanese family identifies a DMRT3-OAS3 interaction that is involved in human sexual differentiation through the regulation of ESR1 expression. Fertility and sterility 10 32553473
2017 The evolutionary history of the DMRT3 'Gait keeper' haplotype. Animal genetics 10 28741731
2016 Comparison of DMRT3 genotypes among American Saddlebred horses with reference to gait. Animal genetics 10 27295976
2024 Curcumin Inhibits the Progression of Non-small Cell Lung Cancer by Regulating DMRT3/SLC7A11 Axis. Molecular biotechnology 7 38744789
2020 Distribution of the mutant allele of the DMRT3 gene associated with ambling gaits in Japanese native horse populations. Animal science journal = Nihon chikusan Gakkaiho 7 32761714
2017 Lack of significant associations with early career performance suggest no link between the DMRT3 "Gait Keeper" mutation and precocity in Coldblooded trotters. PloS one 7 28489879
2021 Transcriptome Analysis Identifies Doublesex and Mab-3 Related Transcription Factor (DMRT3) in Nasal Polyp Epithelial Cells of Patients Suffering from Non-Steroidal Anti-Inflammatory Drug-Exacerbated Respiratory Disease (AERD). Biomolecules 6 34439758
2022 Adult spinal Dmrt3 neurons receive direct somatosensory inputs from ipsi- and contralateral primary afferents and from brainstem motor nuclei. The Journal of comparative neurology 5 36214727
2018 Identification of a candidate enhancer for DMRT3 involved in spastic cerebral palsy pathogenesis. Biochemical and biophysical research communications 5 29305858
2023 Identification and characterization of single nucleotide polymorphisms in DMRT3 gene in Indian horse (Equus caballus) and donkey (Equus asinus) populations. Animal biotechnology 4 37149793
2024 DMRT3-mediated lncRNA OIP5-AS1 promotes the pyroptosis of bronchial epithelial cells by binding with EIF4A3 to enhance YAP mRNA stability. Immunologic research 3 39287912
2023 The genetics of gaits in Icelandic horses goes beyond DMRT3, with RELN and STAU2 identified as two new candidate genes. Genetics, selection, evolution : GSE 3 38082412
2020 A novel simple genotyping assay for detection of the 'Gait keeper' mutation in DMRT3 and allele frequencies in Azteca and Costa Rican Saddle Horse breeds. Molecular and cellular probes 2 31917254
2026 DMRT3 gene variations in horse breeds selected for gaited movement - established research and novel findings. Journal of equine veterinary science 0 41936970
2019 Correction: Selection on the Colombian paso horse's gaits has produced kinematic differences partly explained by the DMRT3 gene. PloS one 0 30726296