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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]

Gene

In humans, the DMRT1 gene is located at the end of chromosome 9. This gene is found in a cluster with two other members of the gene family.

In birds, DMRT1 is located on the Z chromosome and male sexual development is determined by dosage of this gene.[8]

Structure

DMRT1 belongs to a gene family characterized by a zinc finger-like DNA-binding motif known as the 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 birds.[9]

The majority of DMRT1 protein is located in the testicular cord and Sertoli cells, with a small amount present in germ cells.

Function

DMRT1 is a dose-sensitive transcription factor that regulates Sertoli cells and germ cells.

Two copies of the DMRT1 gene are required for normal sexual development. The gene is critical for male sex determination; in its absence, female developmental pathways predominate and male characteristics are reduced or absent.

When DMRT1 is knocked out in mice, changes occur in both Sertoli and germ cells soon after formation of the gonadal ridge. The principal defects associated with DMRT1 knockout include developmental arrest, excess proliferation of germ cells, and failure to undergo meiosis, mitosis, or migration. Thus, the knockout model shows that loss of DMRT1 is associated with incomplete germ cell development leading to infertility, abnormal testicular formation, and/or feminization of the affected individual.[citation needed]

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 ordinarily found in the ovary.[10]

Conversely, conditional expression of DMRT1 in the gonad of female mice caused apparent transdifferentiation of ovarian somatic (granulosa) cells to the equivalent male cell type (Sertoli).[11]

Clinical significance

Defective testicular development and XY feminization occur when this gene is hemizygous.[5]

Loss of one copy of DMRT1 most commonly occurs in chromosome 9p deletion, which causes abnormal testicular formation and feminization.

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000137090 – Ensembl, May 2017
  2. ^ a b c 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. ^ a b “Entrez Gene: DMRT1 doublesex and mab-3 related transcription factor 1”.
  6. ^ Raymond CS, Shamu CE, Shen MM, Seifert KJ, Hirsch B, Hodgkin J, et al. (February 1998). “Evidence for evolutionary conservation of sex-determining genes”. Nature. 391 (6668): 691–695. Bibcode:1998Natur.391..691R. doi:10.1038/35618. PMID 9490411. S2CID 11414843.
  7. ^ Raymond CS, Parker ED, Kettlewell JR, Brown LG, Page DC, Kusz K, et al. (June 1999). “A region of human chromosome 9p required for testis development contains two genes related to known sexual regulators”. Human Molecular Genetics. 8 (6): 989–996. doi:10.1093/hmg/8.6.989. PMID 10332030.
  8. ^ Wilson J, Staley JM, Wyckoff GJ (February 2020). “Extinction of chromosomes due to specialization is a universal occurrence”. Scientific Reports. 10 (1) 2170. Bibcode:2020NatSR..10.2170W. doi:10.1038/s41598-020-58997-2. PMC 7005762. PMID 32034231.
  9. ^ Smith CA, Roeszler KN, Ohnesorg T, Cummins DM, Farlie PG, Doran TJ, et al. (August 2009). “The avian Z-linked gene DMRT1 is required for male sex determination in the chicken”. Nature. 461 (7261): 267–271. Bibcode:2009Natur.461..267S. doi:10.1038/nature08298. PMID 19710650. S2CID 4413389.
  10. ^ 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): 101–104. doi:10.1038/nature10239. PMC 3150961. PMID 21775990.
  11. ^ Lindeman RE, Gearhart MD, Minkina A, Krentz AD, Bardwell VJ, Zarkower D (March 2015). “Sexual cell-fate reprogramming in the ovary by DMRT1”. Current Biology. 25 (6): 764–771. Bibcode:2015CBio…25..764L. doi:10.1016/j.cub.2015.01.034. PMC 4366330. PMID 25683803.

Further reading

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