The Mammalian Doublesex Homolog DMRT1 is a Transcriptional Gatekeeper That Controls the Mitosis Versus Meiosis Decision in Male Germ Cells

Overview

Journal Dev Cell

Publisher Cell Press

Specialties Cell Biology
Reproductive Medicine

Date 2010 Oct 19

PMID 20951351

Citations 149

Authors

Clinton K Matson

Mark W Murphy

Michael D Griswold

Shosei Yoshida

Vivian J Bardwell

David Zarkower

Affiliations

Soon will be listed here.

Abstract

The switch from mitosis to meiosis is a unique feature of germ cell development. In mammals, meiotic initiation requires retinoic acid (RA), which activates meiotic inducers, including Stra8, but how the switch to meiosis is controlled in male germ cells (spermatogonia) remains poorly understood. Here we examine the role of the Doublesex-related transcription factor DMRT1 in adult spermatogenesis using conditional gene targeting in the mouse. Loss of Dmrt1 causes spermatogonia to precociously exit the spermatogonial program and enter meiosis. Therefore, DMRT1 determines whether male germ cells undergo mitosis and spermatogonial differentiation or meiosis. Loss of Dmrt1 in spermatogonia also disrupts cyclical gene expression in Sertoli cells. DMRT1 acts in spermatogonia to restrict RA responsiveness, directly repress Stra8 transcription, and activate transcription of the spermatogonial differentiation factor Sohlh1, thereby preventing meiosis and promoting spermatogonial development. By coordinating spermatogonial development and mitotic amplification with meiosis, DMRT1 allows abundant, continuous production of sperm.

Citing Articles

Intercellular bridges are essential for transposon repression and meiosis in the male germline.

Sorkin J, Tilton K, Lawlor M, Sarathy S, Liang S, Albanese A Nat Commun. 2025; 16(1):1488.

PMID: 39929837 PMC: 11811169. DOI: 10.1038/s41467-025-56742-9.

Both 20S and 19S proteasome components are essential for meiosis in male mice.

Han T, Wang L, Zhou Q, Wei W, Ma Y, Chen Y Zool Res. 2025; 46(1):27-40.

PMID: 39757018 PMC: 11891003. DOI: 10.24272/j.issn.2095-8137.2024.281.

2-Bromopalmitate-Induced Intestinal Flora Changes and Testicular Dysfunction in Mice.

Ma Y, Chen Y, Li L, Wu Z, Cao H, Zhu C Int J Mol Sci. 2024; 25(21).

PMID: 39518967 PMC: 11547043. DOI: 10.3390/ijms252111415.

Dynamic transcriptomic and regulatory networks underpinning the transition from fetal primordial germ cells to spermatogonia in mice.

Zhao J, Tang K, Jiang G, Yang X, Cui M, Wan C Cell Prolif. 2024; 58(2):e13755.

PMID: 39329203 PMC: 11839193. DOI: 10.1111/cpr.13755.

The Role of Retinoic Acid in Spermatogenesis and Its Application in Male Reproduction.

Zhao Y, Deng S, Li C, Cao J, Wu A, Chen M Cells. 2024; 13(13.

PMID: 38994945 PMC: 11240464. DOI: 10.3390/cells13131092.

References

Krentz A, Murphy M, Kim S, Cook M, Capel B, Zhu R . The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency. Proc Natl Acad Sci U S A. 2009; 106(52):22323-8. PMC: 2799724. DOI: 10.1073/pnas.0905431106. View

van Pelt A, de Rooij D . Synchronization of the seminiferous epithelium after vitamin A replacement in vitamin A-deficient mice. Biol Reprod. 1990; 43(3):363-67. DOI: 10.1095/biolreprod43.3.363. View

Reynolds N, Collier B, Maratou K, Bingham V, Speed R, Taggart M . Dazl binds in vivo to specific transcripts and can regulate the pre-meiotic translation of Mvh in germ cells. Hum Mol Genet. 2005; 14(24):3899-909. DOI: 10.1093/hmg/ddi414. View

Suzuki A, Saga Y . Nanos2 suppresses meiosis and promotes male germ cell differentiation. Genes Dev. 2008; 22(4):430-5. PMC: 2238665. DOI: 10.1101/gad.1612708. View

Budhu A, Noy N . Direct channeling of retinoic acid between cellular retinoic acid-binding protein II and retinoic acid receptor sensitizes mammary carcinoma cells to retinoic acid-induced growth arrest. Mol Cell Biol. 2002; 22(8):2632-41. PMC: 133717. DOI: 10.1128/MCB.22.8.2632-2641.2002. View

Koshimizu U, Watanabe D, Sawada K, Nishimune Y . A novel stage-specific differentiation antigen is expressed on mouse testicular germ cells during early meiotic prophase. Biol Reprod. 1993; 49(5):875-84. DOI: 10.1095/biolreprod49.5.875. View

Sada A, Suzuki A, Suzuki H, Saga Y . The RNA-binding protein NANOS2 is required to maintain murine spermatogonial stem cells. Science. 2009; 325(5946):1394-8. DOI: 10.1126/science.1172645. View

Handel M, Schimenti J . Genetics of mammalian meiosis: regulation, dynamics and impact on fertility. Nat Rev Genet. 2010; 11(2):124-36. DOI: 10.1038/nrg2723. View

Oulad-Abdelghani M, Bouillet P, Decimo D, Gansmuller A, Heyberger S, Dolle P . Characterization of a premeiotic germ cell-specific cytoplasmic protein encoded by Stra8, a novel retinoic acid-responsive gene. J Cell Biol. 1996; 135(2):469-77. PMC: 2121034. DOI: 10.1083/jcb.135.2.469. View

10.

Hess R, de Franca L . Spermatogenesis and cycle of the seminiferous epithelium. Adv Exp Med Biol. 2009; 636:1-15. DOI: 10.1007/978-0-387-09597-4_1. View

11.

Timmons P, Rigby P, Poirier F . The murine seminiferous epithelial cycle is pre-figured in the Sertoli cells of the embryonic testis. Development. 2002; 129(3):635-47. DOI: 10.1242/dev.129.3.635. View

12.

Vernet N, Dennefeld C, Guillou F, Chambon P, Ghyselinck N, Mark M . Prepubertal testis development relies on retinoic acid but not rexinoid receptors in Sertoli cells. EMBO J. 2006; 25(24):5816-25. PMC: 1698894. DOI: 10.1038/sj.emboj.7601447. View

13.

Ballow D, Meistrich M, Matzuk M, Rajkovic A . Sohlh1 is essential for spermatogonial differentiation. Dev Biol. 2006; 294(1):161-7. DOI: 10.1016/j.ydbio.2006.02.027. View

14.

Anderson E, Baltus A, Roepers-Gajadien H, Hassold T, de Rooij D, van Pelt A . Stra8 and its inducer, retinoic acid, regulate meiotic initiation in both spermatogenesis and oogenesis in mice. Proc Natl Acad Sci U S A. 2008; 105(39):14976-80. PMC: 2542382. DOI: 10.1073/pnas.0807297105. View

15.

Takubo K, Ohmura M, Azuma M, Nagamatsu G, Yamada W, Arai F . Stem cell defects in ATM-deficient undifferentiated spermatogonia through DNA damage-induced cell-cycle arrest. Cell Stem Cell. 2008; 2(2):170-82. DOI: 10.1016/j.stem.2007.10.023. View

16.

Yoshida S, Takakura A, Ohbo K, Abe K, Wakabayashi J, Yamamoto M . Neurogenin3 delineates the earliest stages of spermatogenesis in the mouse testis. Dev Biol. 2004; 269(2):447-58. DOI: 10.1016/j.ydbio.2004.01.036. View

17.

RAYMOND C, Murphy M, OSullivan M, Bardwell V, Zarkower D . Dmrt1, a gene related to worm and fly sexual regulators, is required for mammalian testis differentiation. Genes Dev. 2000; 14(20):2587-95. PMC: 316999. DOI: 10.1101/gad.834100. View

18.

Nakagawa T, Sharma M, Nabeshima Y, Braun R, Yoshida S . Functional hierarchy and reversibility within the murine spermatogenic stem cell compartment. Science. 2010; 328(5974):62-7. PMC: 2981100. DOI: 10.1126/science.1182868. View

19.

Yomogida K, Ohtani H, Harigae H, Ito E, Nishimune Y, Engel J . Developmental stage- and spermatogenic cycle-specific expression of transcription factor GATA-1 in mouse Sertoli cells. Development. 1994; 120(7):1759-66. DOI: 10.1242/dev.120.7.1759. View

20.

Noy N . The ionization behavior of retinoic acid in lipid bilayers and in membranes. Biochim Biophys Acta. 1992; 1106(1):159-64. DOI: 10.1016/0005-2736(92)90234-d. View