Abstract
The transition from mitotic to meiotic cell cycles is essential for haploid gamete formation and fertility. Stimulated by retinoic acid gene 8 (Stra8) is an essential gatekeeper of meiotic initiation in vertebrates; yet, the molecular role of STRA8 remains principally unknown. Here we demonstrate that STRA8 functions as a suppressor of autophagy during spermatogenesis in mice. Stra8-deficient germ cells fail to enter meiosis and present aberrant upregulation of autophagy-lysosome genes, commensurate with autophagy activation. Biochemical assays show that ectopic expression of STRA8 alone is sufficient to inhibit both autophagy induction and maturation. Studies also revealed that, Nr1d1, a nuclear hormone receptor gene, is upregulated in Stra8-deficient testes and that STRA8 binds to the Nr1d1 promoter, indicating that Nr1d1 is a direct target of STRA8 transcriptional repression. In addition, it was found that NR1D1 binds to the promoter of Ulk1, a gene essential for autophagy initiation, and that Nr1d1 is required for the upregulated Ulk1 expression in Stra8-deficient testes. Furthermore, both genetic deletion of Nr1d1 and pharmacologic inhibition of NR1D1 by its synthetic antagonist SR8278 exhibit rescuing effects on the meiotic initiation defects observed in Stra8-deficient male germ cells. Together, the data suggest a novel link between STRA8-mediated autophagy suppression and meiotic initiation.
Highlights
Meiosis is a fundamental process in sexual reproduction during which diploid cells halve their chromosome number by two rounds of cell divisions to generate haploid cells or gametes
Meiotic initiation is a key feature of sexual reproduction that launches an intricate chromosomal program involving DNA double strand breaks (DSBs), homolog pairing, cohesion, synapsis, and recombination
Meiotic Gatekeeper STRA8 is a suppressor of autophagy
Summary
Meiosis is a fundamental process in sexual reproduction during which diploid cells halve their chromosome number by two rounds of cell divisions to generate haploid cells or gametes. Stra likely governs both meiotic initiation and early meiotic progression. Stra8-deficient germ cells (exons 2–7 deleted) of both sexes do not display molecular hallmarks of meiotic initiation (e.g., DSBs) and fail to enter meiosis in juvenile mouse testes and in developing ovaries [7, 8]. Another study that used a different Stra8-deficient mouse line, in which exons 2–4 were deleted on an F1 hybrid (C57BL/6 x 129) background showed that Stra functions instead in early meiotic prophase in spermatogenesis [9]. STRA8 is an essential regulator of meiosis that likely acts as a transcription factor, but currently there is little information on its molecular role and functional targets implicated in meiosis [10]
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