(Provided by the applicant) Abstract: Competition between cells within organisms has been recognized in social amoebae, Drosophila, and the inception and metastasis of cancer. "Winner" cells exhibit advantages in growth, adhesion or survival, putatively increasing the overall fitness of the individual organism. However, only competition among germ cells results in direct inheritance of "winner" traits. As gametes are established during early embryonic development from primordial germ cells (PGCs), heritable genetic mutations that undergo selection and drive evolution of species must occur in this cell lineage. I previously demonstrated germline stem cell competition in a basal chordate and recent work hints at a parallel phenomenon in mammals. Our goal is to determine the gene regulatory and genetic bases for germ cell competition in mice. We will study competition among PGCs in the mouse embryo in three aspects of their development: the allocation of pluripotent epiblast cells to the germline, the migration of PGCs to the gonadal ridges, and the expansion of PGCs in the embryonic gonad as they commence sex-specific differentiation. To model in vivo competition among isogenic PGCs, we will employ genetic marking strategies;comparison of "winning" PGC clones to unpurified or non-dominant ones will reveal gene expression and epigenetic differences that potentially bestow an advantage to developing germ cells. To model competitive advantage by genetic alteration, we will employ 7 different PGC mutants that we previously identified in a forward genetic screen of mouse embryos. We will use transplantation approaches to pit these PGC depletion, overabundance and migration phenotypes against one another in vivo and ask how a particular genetic mutation impacts fitness to enter the germline, migrate, and contribute to gamete biogenesis. We hope to gain a molecular understanding of how PGCs interact with their niches and provide insight into basic regulatory and genetic mechanisms of cellular selection that underlie evolution and tumorogenesis. Public Health Relevance: Since the origin and progression of cancer occurs by cells gaining a selective advantage in survival, proliferation or migration, study of the mechanism of cell competition will identify genetic alterations, regulatory or epigenetic changes that become dysregulated in tumor development and could be useful in cancer diagnosis or targeted for therapy. In assisted reproductive technologies, where the prospect of differentiating gametes from pluripotent stem cells looms on the horizon, understanding germ cell competition will be instrumental to informing the potential risks and biological consequences of short circuiting in vivo germ cell development.
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