DMRT1

Doublesex and mab-3 related transcription factor 1, also known as DMRT1, is a protein which in humans is encoded by the DMRT1 gene.[5][6][7]

DMRT1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4YJ0
Identifiers
Aliases	DMRT1, CT154, DMT1, doublesex and mab-3 related transcription factor 1
External IDs	OMIM: 602424 MGI: 1354733 HomoloGene: 9280 GeneCards: DMRT1
Gene location (Human) Chr. Chromosome 9 (human)[1] Band 9p24.3 Start 841,690 bp[1] End 969,090 bp[1]
Gene location (Mouse) Chr. Chromosome 19 (mouse)[2] Band 19|19 B Start 25,505,618 bp[2] End 25,604,329 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • DNA binding • sequence-specific DNA binding • RNA polymerase II regulatory region sequence-specific DNA binding • GO:0001077, GO:0001212, GO:0001213, GO:0001211, GO:0001205 DNA-binding transcription activator activity, RNA polymerase II-specific • chromatin binding • metal ion binding • protein heterodimerization activity • GO:0001158 core promoter proximal region sequence-specific DNA binding • GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity • protein homodimerization activity • identical protein binding • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component • cytoplasm • cell nucleus Biological process • cell differentiation • GO:0007243 intracellular signal transduction • male gonad development • regulation of transcription, DNA-templated • regulation of nodal signaling pathway • Sertoli cell differentiation • positive regulation of meiosis I • negative regulation of transcription from RNA polymerase II promoter • transcription from RNA polymerase II promoter • male sex determination • negative regulation of meiotic nuclear division • Sertoli cell development • oocyte development • transcription, DNA-templated • multicellular organism development • developmental process involved in reproduction • male germ cell proliferation • male sex differentiation • cell morphogenesis • spermatogenesis • positive regulation of mitotic nuclear division • positive regulation of male gonad development • germ cell migration • positive regulation of transcription from RNA polymerase II promoter • sex differentiation Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	1761	50796
Ensembl	ENSG00000137090	ENSMUSG00000024837
UniProt	Q9Y5R6	Q9QZ59
RefSeq (mRNA)	NM_021951 NM_001363767	NM_015826
RefSeq (protein)	NP_068770 NP_001350696	NP_056641
Location (UCSC)	Chr 9: 0.84 – 0.97 Mb	Chr 19: 25.51 – 25.6 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

DMRT1 is a dose sensitive transcription factor protein that regulates Sertoli cells and germ cells. The DMRT1 gene is located at the end of the 9th chromosome. This gene is found in a cluster with two other members of the gene family, having in common a zinc finger-like DNA-binding motif (DM domain). The DM domain is an ancient, conserved component of the vertebrate sex-determining pathway that is also a key regulator of male development in flies and nematodes, and is found to be the key sex-determining factor in chickens.[8] The majority of DMRT1 protein is located in the testicular cord and Sertoli cells, with a small amount in the germ cells.

This gene exhibits a gonad-specific and sexually dimorphic expression pattern, just like the related doublesex gene in fruit flies. Defective testicular development and XY feminization occur when this gene is hemizygous.[5] Two copies of the DMRT1 gene are required for normal sexual development. When a DMRT1 gene is lost, the most common disease is chromosome 9p deletion, which causes abnormal testicular formation and feminization. The DMRT1 gene is critical for male sex determination; without this gene the default female characteristic takes over and male characteristic is slight or non-existent.

When DMRT1 is knocked out in mice, the mice showed changes in both Sertoli and germ cells soon after formation of the gonadal ridge. The main defects associated with DMRT1 knockout were developmental arrest, excess proliferation of germ cells, and failure to undergo meiosis, mitosis, or migration. Thus, the knockout model shows that loss of the DMRT1 gene is associated with incomplete germ cell development leading to infertility, abnormal testicular formation, and/or feminization of the affected individual. Induced knockout of DMRT1 in adult male mice has been found to cause transdifferentiation of somatic cells in the testis to the equivalent cell types that would ordinarily be found in the ovary.[9] Conversely, conditional expression of DMRT1 in the gonad of female mice caused the apparent transdifferentiation of ovarian somatic (granulosa) cells to the equivalent cell type (Sertoli) ordinarily found in males.[10]

References

1. GRCh38: Ensembl release 89: ENSG00000137090 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000024837 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: DMRT1 doublesex and mab-3 related transcription factor 1".
6. Raymond CS, Shamu CE, Shen MM, Seifert KJ, Hirsch B, Hodgkin J, Zarkower D (February 1998). "Evidence for evolutionary conservation of sex-determining genes". Nature. 391 (6668): 691–5. doi:10.1038/35618. PMID 9490411.
7. Raymond CS, Parker ED, Kettlewell JR, Brown LG, Page DC, Kusz K, Jaruzelska J, Reinberg Y, Flejter WL, Bardwell VJ, Hirsch B, Zarkower D (June 1999). "A region of human chromosome 9p required for testis development contains two genes related to known sexual regulators". Hum. Mol. Genet. 8 (6): 989–96. doi:10.1093/hmg/8.6.989. PMID 10332030.
8. Smith CA, Roeszler KN, Ohnesorg T, Cummins DM, Farlie PG, Doran TJ, Sinclair AH (August 2009). "The avian Z-linked gene DMRT1 is required for male sex determination in the chicken". Nature. 461 (7261): 267–71. doi:10.1038/nature08298. PMID 19710650.
9. Matson CK, Murphy MW, Sarver AL, Griswold MD, Bardwell VJ, Zarkower D (July 2011). "DMRT1 prevents female reprogramming in the postnatal mammalian testis". Nature. 476 (7358): 101–4. doi:10.1038/nature10239. PMC 3150961. PMID 21775990.
10. Lindeman RE, Gearhart MD, Minkina A, Krentz AD, Bardwell VJ, Zarkower D (March 2015). "Sexual cell-fate reprogramming in the ovary by DMRT1". Curr Biol. 25 (6): 764–71. doi:10.1016/j.cub.2015.01.034. PMC 4366330. PMID 25683803.

1. Anthony D. Krentza,b, Mark W. Murphya, Shinseog Kima,1, Matthew S. Cookc, Blanche Capelc, Rui Zhud, Angabin Matind, Aaron L. Sarvere, Keith L. Parkerf, Michael D. Griswoldg, Leendert H. J. Looijengah, Vivian J. Bardwella and David Zarkower. "The DM Domain Protein DMRT1 Is a Dose-sensitive Regulator of Fetal Germ Cell Proliferation and Pluripotency." The DM Domain Protein DMRT1 Is a Dose-sensitive Regulator of Fetal Germ Cell Proliferation and Pluripotency. PNAS, 29 Oct. 2009. Web. 12 Mar. 2014.
2. Christopher S. Raymond1, Emily D. Parker2, Jae R. Kettlewell1, Laura G. Brown3, David C. Page3, Kamila Kusz4, Jadwiga Jaruzelska4, Yuri Reinberg5, Wendy L. Flejter6, Vivian J. Bardwell1,2, Betsy Hirsch7 and David Zarkower1. "Human Molecular Genetics." A Region of Human Chromosome 9p Required for Testis Development Contains Two Genes Related to Known Sexual Regulators. Oxford Journal, n.d. Web. 28 Feb. 2014.
3. Craig A. Smith, Kelly N. Roeszler, Thomas Ohnesorg, David M. Cummins, Peter G. Farlie, Timothy J. Doran & Andrew H. Sinclair. "The Avian Z-linked Gene DMRT1 Is Required for Male Sex Determination in the Chicken." Nature.com. Nature, 26 Aug. 2009. Web. 12 Mar. 2014.
4. "DMRT1 Gene." - GeneCards. Crown Human Genome Center, Department of Molecular Genetics, the Weizmann Institute of Science,http://genome.ucsc.edu/. 23 Oct. 2013. Web. 12 Mar. 2014.
5. Ning Lei, Kaori I. Hornbaker, Daren A. Rice, Tatiana Karpova, Valentine A. Agbor, and Leslie L. Heckert. "Sex-specific Differences in Mouse DMRT1 Expression Are Both Cell Type- and Stage-dependent during Gonad Development." Sex-specific Differences in Mouse DMRT1 Expression Are Both Cell Type- and Stage-dependent during Gonad Development. NIH Public Access, 13 June 2007. Web. 12 Mar. 2014.

Further reading

• Smith CA, McClive PJ, Western PS, et al. (2000). "Conservation of a sex-determining gene". Nature. 402 (6762): 601–2. doi:10.1038/45127. PMID 10604464.
• Calvari V, Bertini V, De Grandi A, et al. (2000). "A new submicroscopic deletion that refines the 9p region for sex reversal". Genomics. 65 (3): 203–12. doi:10.1006/geno.2000.6160. PMID 10857744.
• Muroya K, Okuyama T, Goishi K, et al. (2000). "Sex-determining gene(s) on distal 9p: clinical and molecular studies in six cases". J. Clin. Endocrinol. Metab. 85 (9): 3094–100. doi:10.1210/jc.85.9.3094. PMID 10999792.
• Raymond CS, Murphy MW, O'Sullivan MG, et al. (2000). "Dmrt1, a gene related to worm and fly sexual regulators, is required for mammalian testis differentiation". Genes Dev. 14 (20): 2587–95. doi:10.1101/gad.834100. PMC 316999. PMID 11040213.
• Casci T (2001). "It's a guy thing". Nat. Rev. Genet. 1 (3): 169. doi:10.1038/35042034. PMID 11252745.
• Harrington JJ, Sherf B, Rundlett S, et al. (2001). "Creation of genome-wide protein expression libraries using random activation of gene expression". Nat. Biotechnol. 19 (5): 440–5. doi:10.1038/88107. PMID 11329013.
• Boyer A, Dornan S, Daneau I, et al. (2004). "Conservation of the function of DMRT1 regulatory sequences in mammalian sex differentiation". Genesis. 34 (4): 236–43. doi:10.1002/gene.10158. PMID 12434333.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Humphray SJ, Oliver K, Hunt AR, et al. (2004). "DNA sequence and analysis of human chromosome 9". Nature. 429 (6990): 369–74. doi:10.1038/nature02465. PMC 2734081. PMID 15164053.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
• Cheng HH, Ying M, Tian YH, et al. (2006). "Transcriptional diversity of DMRT1 (dsx- and mab3-related transcription factor 1) in human testis". Cell Res. 16 (4): 389–93. doi:10.1038/sj.cr.7310050. PMID 16617334.
• *1. A region of human chromosome 9p required for testis development contains two genes related to known sexual regulators. (PubMed id 10332030)1, 2, 3, 9 Raymond C.S.... Zarkower D. (1999)
• 2. Evidence for evolutionary conservation of sex-determining genes. (PubMed id 9490411)1, 2, 3, 9 Raymond C.S....Zarkower D. (1998)
• 3. Variants near DMRT1, TERT and ATF7IP are associated with testicular germ cell cancer. (PubMed id 20543847)1, 2, 4 Turnbull C....Rahman N. (2010)
• 4. Transcriptional diversity of DMRT1 (dsx- and mab3-related transcription factor 1) in human testis. (PubMed id 16617334)1, 2, 9 Cheng H.H....Zhou R.J. (2006)
• 5. A new submicroscopic deletion that refines the 9p region for sex reversal. (PubMed id 10857744)1, 2, 9 Calvari V.... Guioli S. (2000)
• 6. A second independent locus within DMRT1 is associated with testicular germ cell tumor susceptibility. (PubMed id 21551455)1, 4 Kanetsky P.A....Nathanson K.L. (2011)
• 7. Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score. (PubMed id 20379614)1, 4 Rose J.E....Uhl G.R. (2010)
• 8. DNA sequence and analysis of human chromosome 9. (PubMed id 15164053)1, 2 Humphray S.J.... Dunham I. (2004)
• 9. The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). (PubMed id 15489334)1,2 Gerhard D.S....Malek J. (2004)
• 10. The DM domain protein DMRT1 is a dose-sensitive regul ator of fetal germ cell proliferation and pluripotency. (PubMed id 20007774)1, 9 Krentz A.D....Zarkower D. (2009)

External links

• DMRT1+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)
• https://web.archive.org/web/20110720091853/http://www.dmrt1.umn.edu/
• Overview of all the structural information available in the PDB for UniProt: Q9Y5R6 (Doublesex- and mab-3-related transcription factor 1) at the PDBe-KB.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.