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

• 批准号: 10303387
• 负责人: Jeremy Nance
• 金额: $ 21.19万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303387
• 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

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.

总结 详细了解生殖细胞发育的每一步对于理解发育过程至关重要。 人类不育的基础，达到配子体外分化的目的。原始生殖细胞 （PGCs）是产生精子和卵子的胚胎前体细胞，因此对于发育至关重要。 生育在早期胚胎发生过程中，PGCs进入细胞周期和转录调控的临时时期， 这对保持他们的发展潜力很重要。随后，PGCs增殖， 分化成生殖干细胞以产生配子。这些监管活动的指导原则是： 对体细胞龛产生的信号知之甚少。例如，哺乳动物PGCs接受关键的，但 来自生殖嵴的不明分化信号。我们对利基信号是如何 调节PGC的部分原因是缺乏模型系统，其中小生境-PGC相互作用可以 在分子细节上进行了研究。 我们的长期目标是利用C语言的实验优势。来确定体细胞生态位 胚胎中的细胞调节PGC静止。许多关于生殖细胞的基本和保守的见解 生物学来自于对无脊椎动物模型的研究，包括C。优美的胚胎含有两个原始生殖细胞， 它们由两个体细胞性腺细胞（SGPs）连接形成原始性腺。SGPs作为一个利基市场， 确保PGCs保持静止直到胚胎孵化。我们发现，SGPs在以下情况下实现了这一点： 两种方式。首先，它们需要模板化围绕原始细胞的基底膜（BM 生殖腺其次，它们需要传递来自性腺BM的信号，该信号阻止胚胎发育。 PGCs退出静止。虽然信号的身份是未知的，但PGC静止的损失， 当BM耗尽时，伴随着Notch信号通路的激活， GLP-1 Notch受体的突变。我们的中心假设是，BM通过以下方式维持PGC静止： 抑制SGPs中的Notch配体，防止其激活PGCs中的GLP-1受体。具体 该建议的目的是鉴定SGP Notch配体和BM蛋白和受体， 调节PGC静止，并确定BM和Notch信号传导组分如何相互作用。这些 基础研究将使我们能够开发C.将线虫的性腺原基转化为一个强大的新模型 系统，以研究PGC的小生境信号转导的分子基础。我们的发现将揭示特定的新的 深入了解生态位BM如何控制Notch信号传导以保持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器。