Defining the Mechanism of Meiotic Initiation Through Autophagy Pathway

项目摘要 精子数量和质量差是男性不育的主要原因，影响全球约7%的男性。雄性育性 取决于二倍体生殖细胞（精原细胞）转化为单倍体精子（精子）。减数分裂 起始是这一过程中的决定性步骤，围绕着从有丝分裂到减数分裂的细胞周期的转变， 需要激活减数分裂前期I的染色体事件所需的减数分裂基因。迄今为止， 哺乳动物减数分裂起始的特征性看门人被视黄酸基因8（Stra 8）刺激，因为 Stra 8 P-/-P生殖细胞不能表达减数分裂基因的子集，并且不进入减数分裂。我们最近的研究表明 STRA 8作为自噬抑制因子的一种新的分子作用，表明减数分裂起始与 和自噬，一种蛋白质和细胞器降解过程。基于这些信息，我们假设 STRA 8介导的自噬抑制使减数分裂基因所需的蛋白质积累， 激活和起始;在没有STRA 8的情况下，这些蛋白质通过自噬降解，阻止减数分裂。 为了验证我们的假设，我们将：1）研究自噬在STRA 8介导的减数分裂起始中的作用。（二） 定义了自噬和减数分裂起始之间的分子联系。总之，我们的研究将建立自噬 作为一个尚未认识到的减数分裂起始调节因子，并发现自噬敏感蛋白， 在哺乳动物的这一过程中的重要分子步骤。通过更好地了解自噬 作为减数分裂诱导的障碍，我们的研究将为体外配子提供重大的技术进步 生产最终，我们研究的翻译可能会在自噬途径中发现新的治疗靶点。 用于男性不育或避孕治疗。

PROJECT SUMMARY 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.