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

• Published in: PLoS genetics 2019-05, Vol.15 (5), p.e1008084-e1008084
• Main Authors: Ferder, Ianina C, Fung, Leslie, Ohguchi, Yasuyo, Zhang, Xiaoyu, Lassen, Kara G, Capen, Diane, Brown, Dennis, Xavier, Ramnik J, Wang, Ning
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - deficiency; Adaptor Proteins, Signal Transducing - genetics; Animals; Apoptosis; Autophagy; Autophagy (Cytology); Autophagy - genetics; Autophagy-Related Protein-1 Homolog - genetics; Autophagy-Related Protein-1 Homolog - metabolism; Base Sequence; Biochemistry; Biology; Biology and Life Sciences; Cell death; Chromosomes; Clonal deletion; Deoxyribonucleic acid; DNA; DNA damage; Ectopic expression; Fertility - genetics; Funding; Gene expression; Gene Expression Regulation, Developmental; Gene silencing; Genes; Genetic aspects; Genetic research; Germ cells; Hormones; Isoquinolines - pharmacology; Male; Mammals; Medical schools; Medicine and Health Sciences; Meiosis; Mice; Mice, Inbred C57BL; Mice, Knockout; Novels; Nuclear Receptor Subfamily 1, Group D, Member 1 - antagonists & inhibitors; Nuclear Receptor Subfamily 1, Group D, Member 1 - genetics; Nuclear Receptor Subfamily 1, Group D, Member 1 - metabolism; Observations; Phagocytosis; Physiology; Promoter Regions, Genetic; Protein Binding; Retinoic acid; Sexes; Spermatogenesis; Spermatogenesis - genetics; Spermatozoa - cytology; Spermatozoa - metabolism; Supervision; Testis - cytology; Testis - growth & development; Testis - metabolism; Thiophenes - pharmacology; Transcription activation; Transcription factors; Transmission electron microscopy; Tretinoin; Yeast
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1008084

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.