Control of primordial germ cell quiescence by niche basement membrane and Notch signaling

通过生态位基底膜和Notch信号控制原始生殖细胞静止

基本信息

批准号：
10491811
负责人：
Jeremy Nance
金额：
$ 25.43万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10491811
关键词：
Affect Basement membrane Biological Biological Models Biology Caenorhabditis elegans Cell Communication Cell Cycle Cell Differentiation process Cell membrane Cells Cellular biology Development Embryo Embryonic Development Ensure Environment Event Fertility Foundations GLP-I receptor Genetic Genetic Transcription Genital Genitalia Germ Cells Goals Gonadal structure Human Image In Vitro Infertility Invertebrates Knowledge Laminin Learning Ligands Link Mammals Membrane Proteins Modeling Molecular Mutation Nature Notch Signaling Pathway Positioning Attribute Primordium Proliferating Regulation Research Signal Pathway Signal Transduction Structure of primordial sex cell System Teratoma Testing Touch sensation base blastomere structure design egg experience experimental study germline stem cells glucagon-like peptide 1 insight notch protein precursor cell preservation prevent programs receptor recruit sperm cell stem cells

项目摘要

SUMMARY A detailed knowledge of each step of germ cell development is critical for understanding the developmental basis of human infertility and for reaching the goal of differentiating gametes in vitro. Primordial germ cells (PGCs) are the embryonic precursor cells that give rise to sperm and eggs, and are therefore essential for fertility. During early embryogenesis, PGCs enter a temporary period of cell cycle and transcriptional quiescence that is important for preserving their developmental potential. Subsequently, PGCs proliferate then differentiate into germline stem cells in order to produce gametes. These regulatory events are guided by poorly understood signals arising from somatic niches. For example, mammalian PGCs receive critical but unidentified differentiation signals from the genital ridge. Our poor understanding of how niche signaling regulates PGCs is due in part to the paucity of model systems in which niche-PGC interactions can been investigated in molecular detail. Our long-term goal is to use the experimental strengths of C. elegans to determine how somatic niche cells in the embryo regulate PGC quiescence. Many fundamental and deeply conserved insights into germ cell biology have come from studies in invertebrate models, including C. elegans. Embryos contain two PGCs, which are enwrapped by two somatic gonad cells (SGPs) to form the primordial gonad. SGPs act as a niche to ensure that PGCs remain quiescent until the embryo hatches. We have found that SGPs accomplish this in two ways. First, they are required to template a basement membrane (BM) that surrounds the primordial gonad. Second, they are needed to relay a signal originating from the gonadal BM that prevents embryonic PGCs from exiting quiescence. While the identity of the signal is unknown, the loss of PGC quiescence that occurs when BM is depleted is accompanied by activation of the Notch signaling pathway and is suppressed by mutations in the GLP-1 Notch receptor. Our central hypothesis is that BM maintains PGC quiescence by inhibiting a Notch ligand in SGPs, preventing it from activating the GLP-1 receptor in PGCs. The specific objectives of this proposal are to identify the SGP Notch ligand and the BM proteins and receptors that regulate PGC quiescence, and to determine how BM and Notch signaling components interface. These foundational studies will enable us to develop the C. elegans gonad primordium into a powerful new model system to investigate the molecular basis of niche signaling to PGCs. Our findings will reveal specific new insights into how niche BM controls Notch signaling to preserve PGC quiescence, informing studies of mammalian PGC regulation. They will also more broadly illuminate how niche BM can control Notch signaling - a critical regulator of many stem cell systems.

概括详细了解生殖细胞发育的每个步骤对于理解发育过程至关重要人类不育的基础和达到体外分化配子的目标。原始生殖细胞 (PGC) 是产生精子和卵子的胚胎前体细胞，因此对于生育能力。在早期胚胎发生期间，PGC 进入细胞周期和转录的临时时期静止对于保持其发展潜力很重要。随后，PGC 开始增殖分化为生殖干细胞以产生配子。这些监管事件的指导体细胞生态位产生的信号知之甚少。例如，哺乳动物 PGC 受到关键但来自生殖嵴的未识别分化信号。我们对利基信号如何传递知之甚少调节 PGC 的部分原因是缺乏可以研究利基-PGC 相互作用的模型系统对分子细节进行了研究。我们的长期目标是利用秀丽隐杆线虫的实验优势来确定体细胞生态位如何胚胎中的细胞调节 PGC 静止。关于生殖细胞的许多基本且深入保守的见解生物学来自对无脊椎动物模型的研究，包括线虫。胚胎含有两个 PGC，它们被两个体细胞性腺细胞（SGP）包裹，形成原始性腺。 SGP 作为一个利基市场确保 PGC 保持静止状态直至胚胎孵化。我们发现 SGP 在以下方面实现了这一目标两种方式。首先，他们需要模板化围绕原始细胞的基底膜（BM）性腺。其次，它们需要传递来自性腺 BM 的信号，以阻止胚胎发育。 PGC 退出静止状态。虽然信号的身份未知，但 PGC 静止的丧失表明当 BM 耗尽时发生，伴随着 Notch 信号通路的激活并被抑制 GLP-1 Notch 受体突变。我们的中心假设是 BM 通过以下方式维持 PGC 静止：抑制 SGP 中的 Notch 配体，防止其激活 PGC 中的 GLP-1 受体。具体的该提案的目的是鉴定 SGP Notch 配体以及 BM 蛋白和受体调节 PGC 静止，并确定 BM 和 Notch 信号传导成分如何相互作用。这些基础研究将使我们能够将线虫性腺原基发展成一个强大的新模型系统研究 PGCs 生态位信号传导的分子基础。我们的研究结果将揭示具体的新深入了解利基 BM 如何控制 Notch 信号以保持 PGC 静止，为以下研究提供信息哺乳动物 PGC 调节。他们还将更广泛地阐明利基 BM 如何控制 Notch 信号传导 - 许多干细胞系统的关键调节剂。