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Maternal control of germline development

种系发育的母体控制

基本信息

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
项目类别：
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

项目摘要

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）是配子的前体。 PGC 发育缺陷会导致生殖细胞减少或消除，最终导致人类不育，影响 10-15% 情侣。在发育过程中，PGC 的诞生比性腺的形成要早得多。 PGC 必须设法在无保护的体细胞环境中长期生存并随后长期迁徙寻找性腺的距离。 PGC 的规范及其早期增殖至关重要以确保有足够数量的PGC能够到达性腺并分化成配子。一个大大量文献表明，在迁移到性腺之前，PGC 的发育在很大程度上依赖于关于翻译和翻译后调节机制。了解 PGC 的开发过程因此，在翻译和翻译后水平上操作与人类生殖高度相关健康。我的实验室使用非洲爪蟾作为模型来研究早期 PGC 的发育。我们最近报道了母体 Dead End1 (Dnd1) 对于卵母细胞中 mRNA 的不对称定位非常重要。后受精时，Dnd1 招募 nanos mRNA 的翻译机制并促进 nanos 翻译。通过这种机制，Dnd1 可以阻止 PGC 的体细胞分化并保护其全能性。我们最近的初步结果表明，Dnd1 在卵母细胞中被泛素快速降解。独立的蛋白酶体系统。为了让Dnd1积累并促进nanos翻译后受精、编码蛋白酶体激活剂的 RNA 必须与 dnd1 和其他种系分开卵母细胞到胚胎转变过程中的特定母体因素。我们建议研究一下这部小说 mRNA易位事件为受精后PGC发育的启动做好准备并进行研究如何将编码蛋白酶体激活剂的 RNA 与 dnd1 和其他种系特异性母体分离卵母细胞向胚胎转变过程中的因素。此外，我们还得到了一个令人兴奋的发现，即第一个 PGC 增殖波受母体 Dzip1 调节。我们将确定 Dzip1 是否监管 PGC 通过结合和改变种系特异性RNA结合蛋白的活性来增殖。此外，我们将确定作用于 Dzip1 下游以控制的合子转录网络 PGC 增殖。这些工作将为我们理解基本细胞、生殖和发育生物学。