Poor sperm quantity and quality are major causes of male infertility, affecting ~7% of men worldwide. Male fertility depends on the conversion of diploid germ cells (spermatogonia) into haploid spermatozoa (sperm). Meiotic initiation, a defining step in this process, revolves around the transition from mitotic to meiotic cell cycles and entails activation of meiotic genes required for the chromosomal events of meiosis prophase I. To date, a best characterized gatekeeper of meiotic initiation in mammals is stimulated by retinoic acid gene 8 (Stra8), in that Stra8P?/?P germ cells fail to express a subset of meiotic genes and do not enter meiosis. Our recent work indicates a novel molecular role of STRA8 as a suppressor of autophagy, suggesting a novel link between meiotic initiation and autophagy, a protein and cellular organelle degradation process. Based on this information, we hypothesize that STRA8-mediated suppression of autophagy allows accumulation of proteins required for meiotic gene activation and initiation; in the absence of STRA8, these proteins are degraded by autophagy, precluding meiosis. To test our hypothesis, we will: 1) investigate the role of autophagy in STRA8-mediated meiotic initiation. 2) define the molecular links between autophagy and meiotic initiation. Together, our study will establish autophagy as a yet unrecognized regulator of meiotic initiation and uncover autophagy-sensitive proteins that serve as essential molecular steps during this process in mammals. By developing a better understanding of autophagy as a barrier to meiotic induction, our study will offer a significant technical advancement for in vitro gamete production. Ultimately, translation of our study may identify novel therapeutic targets in the autophagy pathway for male infertility or contraception treatment.
A gap of knowledge exists in haploid sperm formation with regard to how male germ cells initiate meiotic cell cycle for homologous recombination and reduction of chromosome content. In this project, the investigators will determine the novel role of autophagy, a protein and cellular organelle recycling process, in regulating meiotic initiation. In addition to providing new research directions in studying this process unique to sex cells, the study will offer new approaches for the treatment of male infertility, contraception, and production of haploid sperm cells in culture.
