Abstract
In mammals, germ cells within the developing gonad follow a sexually dimorphic pathway. Germ cells in the murine ovary enter meiotic prophase during embryogenesis, whereas germ cells in the embryonic testis arrest in G0 of mitotic cell cycle and do not enter meiosis until after birth. In mice, retinoic acid (RA) signaling has been implicated in controlling entry into meiosis in germ cells, as meiosis in male embryonic germ cells is blocked by the activity of a RA-catabolizing enzyme, CYP26B1. However, the mechanisms regulating mitotic arrest in male germ cells are not well understood. Cyp26b1 expression in the testes begins in somatic cells at embryonic day (E) 11.5, prior to mitotic arrest, and persists throughout fetal development. Here, we show that Sertoli cell-specific loss of CYP26B1 activity between E15.5 and E16.5, several days after germ cell sex determination, causes male germ cells to exit from G0, re-enter the mitotic cell cycle and initiate meiotic prophase. These results suggest that male germ cells retain the developmental potential to differentiate in meiosis until at least at E15.5. CYP26B1 in Sertoli cells acts as a masculinizing factor to arrest male germ cells in the G0 phase of the cell cycle and prevents them from entering meiosis, and thus is essential for the maintenance of the undifferentiated state of male germ cells during embryonic development.
Highlights
Retinoic acid (RA) is a vitamin A derived signaling molecule that regulates cell proliferation, migration, and differentiation during embryonic development and adult homeostasis
Genotyping was performed using appropriate primers, and excision of Cyp26b1 was detected only in the testes of Cyp26b1SC2/SC2 animals (Figure 1B, 364 bp band). It should be noted in the testes of Cyp26b1SC2/SC2 mice, a band corresponding to a floxed Cyp26b1 allele was still detected by PCR (Figure 1B, 284 bp band). This may indicate that there was not 100% excision of the Cyp26b1fl/fl locus, or may reflect amplification of DNA extracted from non-Sertoli cells in the testes
We previously reported that genetic deletion of Cyp26b1 by E11.5, prior to the germ cell sex determination, leads to increased RA levels in the embryonic testes resulting in premature meiotic initiation and apoptosis in male germ cells [9]
Summary
Retinoic acid (RA) is a vitamin A derived signaling molecule that regulates cell proliferation, migration, and differentiation during embryonic development and adult homeostasis. RAmediated signaling is controlled in embryonic tissues through coordinated regulation of RA synthesis and catabolism. Synthesis is catalyzed by a family of retinaldehyde dehydrogenases (ALDH1A1, ALDH1A2 and ALDH1A3) that irreversibly oxidize retinal to form RA, while catabolism is facilitated by a family of cytochrome P450 enzymes (CYP26A1, CYP26B1 and CYP26C1), which convert RA to more polar, inactive metabolites [1,2]. Gene targeting studies have demonstrated that changing the endogenous distribution of RA can have severe consequences for the developing embryo. Aldh1a22/2 embryos die around embryonic day (E) 10.5 and display phenotypes resembling severe maternal vitamin A deficiency, while Cyp26a1 and Cyp26b1 null embryos exhibit numerous malformations reminiscent of RA teratogenicity [3,4,5,6,7,8]
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