The mammalian doublesex homolog DMRT1 is a transcriptional gatekeeper that controls the mitosis versus meiosis decision in male germ cells.
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.
Matson
Clinton K
CK
Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455, USA.
Murphy
Mark W
MW
Griswold
Michael D
MD
Yoshida
Shosei
S
Bardwell
Vivian J
VJ
Zarkower
David
D
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000737:chemistry*; D029721:Drosophila Proteins / Q000737:chemistry*; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D007700:Kinetics; D008297:Male; D008540:Meiosis / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D008938:Mitosis / Q000187:drug effects / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D011506:Proteins / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D012708:Sertoli Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013091:Spermatogenesis / Q000187:drug effects / Q000235:genetics; D013093:Spermatogonia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013094:Spermatozoa / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; C110547:DMRT1 protein; D004268:DNA-Binding Proteins; C070369:DSX protein, Drosophila; D029721:Drosophila Proteins; D011506:Proteins; C102019:Stra8 protein, mouse; D014157:Transcription Factors; D014212:Tretinoin