Cell competition in the developing mouse germline

描述（由申请人提供） 翻译后摘要：在社会阿米巴原虫，果蝇，癌症的发生和转移的生物体内的细胞之间的竞争已被确认。“赢家”细胞在生长、粘附或存活方面表现出优势，从而增加个体生物体的整体适应性。然而，只有生殖细胞之间的竞争才能直接遗传“赢家”性状。由于配子是在早期胚胎发育期间从原始生殖细胞（PGCs）建立的，因此经历选择并驱动物种进化的可遗传基因突变必须发生在该细胞谱系中。我以前证明了生殖干细胞竞争在一个基础的脊索动物和最近的工作暗示在哺乳动物中的一个平行的现象。我们的目标是确定小鼠生殖细胞竞争的基因调控和遗传基础。我们将研究小鼠胚胎中PGCs之间的竞争在三个方面的发展：多能外胚层细胞的生殖系的分配，PGCs的迁移到性腺嵴，和PGCs在胚胎性腺中的扩张，因为它们开始性别特异性分化。为了模拟同基因PGC之间的体内竞争，我们将采用遗传标记策略;将“获胜”PGC克隆与未纯化或非显性克隆进行比较，将揭示基因表达和表观遗传差异，这些差异可能赋予发育中的生殖细胞优势。为了通过遗传改变来模拟竞争优势，我们将采用我们先前在小鼠胚胎的正向遗传筛选中鉴定的7种不同的PGC突变体。我们将使用移植方法来坑这些PGC消耗，过剩和迁移表型对彼此在体内，并询问如何一个特定的基因突变影响健身进入种系，迁移，并有助于配子生物发生。我们希望从分子水平上了解PGC如何与其生态位相互作用，并深入了解进化和肿瘤发生的细胞选择的基本调控和遗传机制。 公共卫生相关性：由于癌症的起源和进展是通过细胞在存活、增殖或迁移中获得选择性优势而发生的，因此对细胞竞争机制的研究将鉴定在肿瘤发展中变得失调的遗传改变、调节或表观遗传变化，并且可以用于癌症诊断或靶向治疗。在辅助生殖技术中，从多能干细胞中分化配子的前景隐约可见，了解生殖细胞竞争将有助于了解体内生殖细胞发育短路的潜在风险和生物学后果。

DESCRIPTION (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.