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Meiotic Gatekeeper STRA8 Suppresses Autophagy by Repressing Nr1d1 Expression During Spermatogenesis in Mice

Meiotic Gatekeeper STRA8 Suppresses Autophagy by Repressing Nr1d1 Expression During Spermatogenesis in Mice

Ianina C Ferder, Leslie Fung, Yasuyo Ohguchi, Xiaoyu Zhang, Kara G Lassen, Diane Capen, Dennis Brown, Ramnik J Xavier, Ning Wang

PLoS Genet. 2019 May 6;15(5):e1008084.

PMID: 31059511

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1254944665	SR8278		1254944-66-5	Price

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