In mammals, meiosis is initiated at different time points in males and females, but the mechanism underlying this difference is unknown. Female germ cells begin meiosis during embryogenesis. In males, embryonic germ cells undergo G 0 ͞G 1 mitotic cell cycle arrest, and meiosis begins after birth. In mice, the Stimulated by Retinoic Acid Gene 8 (Stra8) has been found to be required for the transition into meiosis in both female and male germ cells. Stra8 is expressed in embryonic ovaries just before meiotic initiation, whereas its expression in testes is first detected after birth. Here we examine the mechanism underlying the sex-specific timing of Stra8 expression and meiotic initiation in mice. Our work shows that signaling by retinoic acid (RA), an active derivative of vitamin A, is required for Stra8 expression and thereby meiotic initiation in embryonic ovaries. We also discovered that RA is sufficient to induce Stra8 expression in embryonic testes and in vitamin Adeficient adult testes in vivo. Finally, our results show that cytochrome p450 (CYP)-mediated RA metabolism prevents premature Stra8 expression in embryonic testes. Treatment with an inhibitor specific to RA-metabolizing enzymes indicates that a cytochrome p450 from the 26 family (CYP26) is responsible for delaying Stra8 expression in embryonic testes. Sex-specific regulation of RA signaling thus plays an essential role in meiotic initiation in embryonic ovaries and precludes its occurrence in embryonic testes. Because RA signaling regulates Stra8 expression in both embryonic ovaries and adult testes, this portion of the meiotic initiation pathway may be identical in both sexes.sex determination
Differentiation of mouse embryonic germ cells as male or female is dependent on the somatic environment of the gonad rather than the sex chromosome constitution of the germ cell. However, little is known about the initiation of germ cell sexual differentiation. Here, we traced the initiation of germ cell sexual differentiation in XX gonads using the Stra8 gene, which we demonstrate is an early molecular marker of female germ cell development. Stra8 is upregulated in embryonic germ cells of XX gonads prior to meiotic entry and is not expressed in male embryonic germ cells. A developmental time course of Stra8 expression in germ cells of XX gonads has revealed an anterior-to-posterior wave of differentiation that lasts approximately 4 days, from embryonic days 12.5 to 16.5. Consistent with these results, we find that embryonic ovarian germ cells upregulate the meiotic gene Dmc1 and downregulate the Oct4 transcription factor in an anterior-to-posterior wave. In complementary experiments, we find that embryonic XX gonads upregulate certain gene markers of somatic female differentiation in an anterior-to-posterior pattern, while others display a center-to-pole pattern of regulation. Thus, sexual differentiation and meiotic entry of germ cells in embryonic XX gonads progress in an anterior-to-posterior pattern that may reflect local environmental cues that are present in the embryonic XX gonad.
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