Migration as a Selection Paradigm for Primordial Germ Cells

项目摘要 细胞异质性，即同一群体中细胞之间的离散差异， 是恶性疾病的诱因然而，细胞异质性对正常细胞的贡献是不确定的。 发展才刚刚开始受到重视。相同细胞之间的微小差异 类型能够确定细胞状态是特别相关的，当考虑到发展的 生殖系原始生殖细胞（PGCs，精子的胚胎前体细胞）的功能异质性 和卵细胞）从一开始就很明显;因为PGCs从它们的特异性位点单独迁移到 性腺脊（Ginsburg等，1990; Kunwar等人，2006年），他们传播到早期迁移的“领导者”， 后来迁移的“落后者”（Gomperts等人，1994年）。此外，并非所有PGC都能到达性腺 许多PGCs沿着迁移路线死亡。性腺脊的成功殖民者 为下一代贡献配子的潜力。离体细胞培养实验表明， 不依赖于组织生态位，PGCs对迁移信号表现出信号反应，这些信号在单个细胞中变化， 水平（Cantú等人，2016）。这些迁移潜力的差异表明，在细胞内可能存在亚型。 PGC的数量是内在决定的，但是这些离散的细胞间差异如何影响 发展未知。领先者和落后者之间的区别可能通过有丝分裂遗传， 转录上不同，并反映了代谢功能的差异。这些初步数据推动了我的总体 假设PGC迁移选择性地有利于更适合的PGC，同时排除那些不太适合的PGC。我 预期稳定的、可遗传的表观遗传状态的丧失、不能进行代谢过程或细胞损伤 可能使PGC不太适合，表现在转录水平上的RNA表达改变。这项建议 旨在描述生殖细胞之间的异质性如何影响发育和生殖能力， 以及迁移是如何确保下一代只存在最高质量细胞的机制。 如何选择PGC来产生下一代尚不清楚。了解PGC的基础 异质性和选择可以揭示发育如何限制配子和形状的传递 传承因此，我认为，PGCs成功地殖民新生性腺不这样做， 随机的机会，而是通过基于迁移的选择，以确保最适合的细胞有助于未来 物种谱系

PROJECT SUMMARY Cellular heterogeneity, the discrete differences between cells within the same population, is recognized as a contributor to malignant conditions. However, the contribution of cellular heterogeneity to normal development is only beginning to be appreciated. The idea that minute differences among cells of the same type are capable of determining cell state is especially pertinent when considering the development of the germline. Functional heterogeneity among primordial germ cells (PGCs, the embryonic precursors to sperm and egg cells) is evident from their inception; as PGCs migrate individually from their site of specification to the gonadal ridges (Ginsburg et al., 1990; Kunwar et al., 2006), they spread into early migratory "Leaders" and later migratory "Laggards" (Gomperts et al., 1994). Additionally, not every PGC will make it to the gonadal ridge; many PGCs die along the migratory route. Successful colonizers of the gonadal ridge maintain the potential to contribute gametes to the next generation. Ex vivo cell culture experiments suggest that independent of tissue niche, PGCs exhibit signaling responses to migratory cues that vary at the single cell level (Cantú et al., 2016). These differences in migratory potential suggest that there may be subtypes within the population of PGCs that are intrinsically determined, but how these discrete cell-to-cell differences impact development is unknown. Distinctions between Leaders and Laggards may be heritable through mitosis, transcriptionally distinct, and reflect differences in metabolic function. These preliminary data fuel my overall hypothesis that PGC migration acts selectively to favor more fit PGCs while excluding those that are less fit. I expect that loss of stable, heritable epigenetic states, inability undergo metabolic processes, or cell damage may render PGCs less fit, manifesting in altered RNA expression at the transcriptional level. This proposal aims to characterize how heterogeneities among germline cells impact development and reproductive capacity, and how migration is a mechanism to ensure only the highest quality cells are present for the next generation. How PGCs are selected to generate the next generation is not known. Understanding the basis of PGC heterogeneity and selection could reveal how development limits the transmission of gametes and shapes inheritance. Therefore, I suggest that PGCs that successfully colonize the nascent gonad do not do so by random chance, but rather through a migration-based selection to ensure the most fit cells contribute to future species lineage.