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.
Bibliographical noteFunding Information:
We thank P. Chambon (IGBMC Strasbourg, France) for STRA8 antibody, H. Tanaka and Y. Nishimune (Osaka University, Japan) for BC7 antibody, A. Rajkovic (University of Pennsylvania) for SOHLH1 antibody, and A. Sarver for bioinformatics assistance. We are grateful to D. Greenstein, A.M. Weber-Main, and J. Kimble for critical reading of the manuscript, A. Bortvin for helpful discussion, and C. Small, K. Takubo, and E. Rahrmann for reagents and technical assistance. This work was supported by grants from the NIH (GM59152) and Minnesota Medical Foundation and an NSF predoctoral fellowship to C.K.M.