Retinoic Acid Activates Two Pathways Required for Meiosis in Mice

Abstract

In all sexually reproducing organisms, cells of the germ line must transition from mitosis to meiosis. In mice, retinoic acid (RA), the extrinsic signal for meiotic initiation, activates transcription of Stra8, which is required for meiotic DNA replication and the subsequent processes of meiotic prophase. Here we report that RA also activates transcription of Rec8, which encodes a component of the cohesin complex that accumulates during meiotic S phase, and which is essential for chromosome synapsis and segregation. This RA induction of Rec8 occurs in parallel with the induction of Stra8, and independently of Stra8 function, and it is conserved between the sexes. Further, RA induction of Rec8, like that of Stra8, requires the germ-cell-intrinsic competence factor Dazl. Our findings strengthen the importance of RA and Dazl in the meiotic transition, provide important details about the Stra8 pathway, and open avenues to investigate early meiosis through analysis of Rec8 induction and function.

Author Summary

The transition from mitosis to meiosis is a defining feature of germ cells, the precursors of eggs and sperm. In mice, retinoic acid (RA), a vitamin A derivative, induces expression of the gene Stra8, which in turn is required for the first critical steps of meiosis. The timing of Stra8 expression in mammalian germ cells is influenced by an RA-degrading enzyme, CYP26B1, that is normally expressed in fetal testes to delay meiosis in males. It is unknown if Stra8 is RA's only meiosis-inducing target in germ cells or if other such genes are regulated by RA independently of Stra8. To investigate this question, we generated two lines of mice: Cyp26b1 mutants and Stra8 mutants. Our genetic experiments comparing germ cell development in these two mutants revealed a new RA target, Rec8. We demonstrate that Rec8 upregulation by RA occurs in the same temporal and spatial manner as Stra8, but Rec8 expression is independent of Stra8. Rec8, like Stra8, plays a critical role during early meiotic processes, suggesting that RA induces meiosis in at least two independent pathways. These findings expand our understanding of the gene regulatory network involved in meiotic initiation in mammals.