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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.

Meiotic gatekeeper STRA8 suppresses autophagy by repressing Nr1d1 expression during spermatogenesis in mice