Maternal control of germline development

种系发育的母体控制

• 批准号: 10410366
• 负责人: Jing Yang
• 金额: $ 38.31万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10410366
• 关键词: Affect; Binding; Cell Proliferation; Cellular biology; Code; Couples; Development; Developmental Biology; Embryo; Ensure; Environment; Event; Fertilization; Genetic Transcription; Germ Cells; Gonadal structure; Human; Infertility; Knowledge; Laboratory Study; Literature; Messenger RNA; Modeling; Oocytes; Proliferating; RNA; RNA-Binding Proteins; Reporting; Reproductive Biology; Reproductive Health; Research; Structure of primordial sex cell; System; Time; Totipotency; Translations; Ubiquitin; Work; Xenopus; egg; gonad development; multicatalytic endopeptidase complex; nano; novel; prevent; recruit; sperm cell; stem cell biology

Abstract Primordial germ cells (PGCs) are the precursors of the gametes. Defective PGC development results in reduction or elimination of germ cells and ultimately causes infertility in humans, which affects 10–15% of couples. During development, PGCs are born much earlier than the formation of the gonads. PGCs must manage to survive in the non-protective somatic environment for a long time and later migrate long distances to find the gonads. Specification of PGCs and their proliferation during early stages are crucial to ensure that sufficient number of PGCs can reach the gonads and differentiate into gametes. A large body of literature has demonstrated that before migrating into the gonads, PGC development relies heavily on translational and post-translational regulatory mechanisms. Understanding how PGC development is operated at the translational and post-translation levels thus is highly relevant to human reproductive health. My laboratory studies early PGC development using Xenopus as a model. We recently reported that maternal Dead End1 (Dnd1) is important for asymmetric localization of mRNA in the oocyte. After fertilization, Dnd1 recruits the translational machinery to nanos mRNA and promotes nanos translation. Through this mechanism, Dnd1 prevents somatic differentiation of PGCs and protects their totipotency. Our recent preliminary results reveal that Dnd1 is rapidly degraded in the oocyte by the ubiquitin- independent proteasome system. In order for Dnd1 to accumulate and promote nanos translation after fertilization, RNAs coding for proteasome activators must be separated from dnd1 and other germline specific maternal factors during the oocyte-to-embryo transition. We propose to study how this novel mRNA translocation event prepares for the initiation of PGC development after fertilization and investigate how RNAs coding for proteasome activators are separated from dnd1 and other germline specific maternal factors during the oocyte-to-embryo transition. Moreover, we have made an exciting finding that the first wave of PGC proliferation is regulated by maternal Dzip1. We will determine if Dzip1 regulates PGC proliferation via binding and modifying the activities of germline specific RNA-binding proteins. Furthermore, we will identify the zygotic transcriptional network that acts downstream of Dzip1 to control PGC proliferation. These works will make important contributions to our understanding of basic cell, reproductive, and developmental biology.

抽象的 原始生殖细胞（PGC）是游戏的前体。 PGC发展有缺陷导致 减少或消除生殖细胞，并最终导致人类不育症，这影响了10-15％ 夫妻。在开发过程中，PGC的出生比性腺的形成要早得多。 PGC必须 设法在非保护躯体环境中生存了很长时间，然后迁移很长时间 找到性腺的距离。 PGC的规格及其在早期阶段的扩散至关重要 为了确保足够数量的PGC可以到达性腺并分化为游戏。一个大 文学机构已经表明，在迁移到性腺之前，PGC的开发很大程度上依赖 关于翻译后的调节机制。了解PGC的发展是如何开发的 因此，在翻译和翻译后水平上经营与人类生殖高度相关 健康。我的实验室研究以xenopus为模型，早期PGC开发。我们最近报道 该材料死端1（DND1）对于在卵母细胞中mRNA的不对称定位很重要。后 受精，DND1将转化机械募集到纳米mRNA并促进纳米翻译。 通过这种机制，DND1防止了PGC的体细胞分化并保护其全能。 我们最近的初步结果表明，DND1迅速通过泛素降解在卵母细胞中。 独立的蛋白酶体系统。为了使DND1在 施肥，编码蛋白酶体激活剂的RNA必须与DND1和其他种系分开 在卵母细胞到胚胎过渡期间的特定材料因素。我们建议研究这部小说 mRNA易位事件为受精后的PGC发展倡议做准备并进行调查 如何将编码蛋白酶体激活剂的RNA与DND1和其他生殖材料分开 卵母细胞到胚胎过渡期间的因素。而且，我们已经提出了一个令人兴奋的发现，第一个 PGC增殖的波受母体DZIP1的调节。我们将确定DZIP1是否调节PGC 通过结合和修饰种系特异性RNA结合蛋白的活性增殖。 此外，我们将确定在DZIP1下游作用的合子转录网络 PGC增殖。这些作品将为我们对基本细胞的理解做出重要贡献， 生殖和发展生物学。