Retinoic Acid Regulates Sex-Specific Timing of Meiotic Initiation in Mice

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 8; pp. 2474 - 2479
• Main Authors: Koubova, Jana, Menke, Douglas B., Zhou, Qing, Capel, Blanche, Griswold, Michael D., Page, David C.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 21-02-2006; National Acad Sciences
• Series: Inaugural Articles
• Subjects: Adaptor Proteins, Signal Transducing; Animals; Biological Sciences; Cytochrome P-450 Enzyme System - metabolism; Embryos; Enzymes; Female; Gene expression regulation; Germ cells; Gonads; Inaugural; Male; Meiosis; Mice; Ovaries; Ovary - drug effects; Ovary - embryology; Ovary - metabolism; Prophase; Proteins - metabolism; Retinoic Acid 4-Hydroxylase; Sex Determination Processes; Somatic cells; Testes; Testis - drug effects; Testis - embryology; Testis - metabolism; Time Factors; Tretinoin - metabolism; Tretinoin - pharmacology; Tretinoin - physiology; Vitamin A Deficiency - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0510813103

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 G₀/G₁ 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.