Molecular genetics of meiotic initiation in mammals

Mammalian fertility is dependent upon meiosis, a specialized cell division by which diploid progenitors undergo one round of DNA replication followed by two rounds of chromosomal segregation to produce haploid gametes. The germ line in the testis and ovary undergoes several rounds of mitotic divisions before ultimately transitioning to the meiotic cell cycle. This transition is achieved by replacing the mitotic cell cycle program with the meiotic one. Here, we discuss the molecular players that regulate the transition from mitosis to meiosis. In spermatogenesis, MEIOC, YTHDC2, and RBM46 form an RNA-binding complex that post-transcriptionally represses the mitotic cell cycle program, while in oogenesis, MEIOC inhibits mitotic cycling prior to meiotic initiation. STRA8 and MEIOSIN act as a transcription factor complex to drive meiotic initiation by upregulating genes involved in cell cycle progression and the unique chromosomal events of meiosis in oogenesis and spermatogenesis. These complexes are activated by upstream molecular players, including transcription factors, epigenetic regulators of chromatin structure, and extrinsic signaling factors, that form an intricate and reinforced molecular network to precisely regulate the transition from the mitotic to meiotic cell cycle. Here, we integrate current knowledge of the regulation of meiotic initiation in mammals and highlight key gaps in this regulatory program that remain to be explored.