Regulation of Mammalian Meiotic Decision by Glutamine Transporter Slc38a2

PROJECT SUMMARY Eukaryotes undergo two primary types of cell division: mitosis and meiosis. Somatic cells rely on mitosis to generate genetically identical daughter cells, while germline cells possess the unique ability to transition from mitosis to meiosis, producing haploid daughter cells with distinct genetic characteristics through meiotic recombination and segregation. Despite the conservation of meiotic genes and chromosome structures across yeasts to mammals, the signals initiating meiosis differ. Yeasts respond to nutrient restriction, which inactivates TOR1/cAMP-dependent protein kinase A (PKA) signaling. On the other hand, mammals require retinoic acid (RA), a chordate morphogen, to activate Stra8 (stimulated by retinoic acid gene 8) for meiosis. We propose a hypothesis that aims to reconcile this evolutionary divergence: nutrient restriction, as a conserved signal, drives meiosis from yeasts to mammals. Specifically, our previous study revealed that mammalian meiosis-initiating cells are influenced by an in vivo autophagy-inducing factor. Subsequent research demonstrated that nutrient restriction, a powerful inducer of autophagy and yeast meiosis as mentioned earlier, induces meiosis in cultured mouse male germline stem cells (mGSCs). Interestingly, our recent transcriptomic study sheds light on how mammalian germ cells "starve themselves" for meiosis in vivo. It shows that during meiotic initiation, nutrient transporter expression is repressed, and this process is facilitated by retinoic acid (RA) and Stra8 through H3K27 deacetylation. Together, these findings suggest that, unlike yeast meiosis, which passively depends on environmental nutrient conditions, mammalian germ cells actively withdraw their nutrient transporters to restrict nutrient uptake and initiate meiosis. In this study, we will: 1) Investigate the role of mTORC1/PKA as signaling hubs connecting Slc38a2 with meiotic initiation; 2) Characterize the metabolic mechanisms that Slc38a2 controls meiotic initiation.