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.

概括 对生殖细胞开发的每个步骤的详细知识对于理解发展性至关重要 人类不育症的基础，并实现在体外区分配子的目标。原始生殖细胞 （PGC）是产生精子和卵的胚胎前体细胞，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间 静止对于保留其发育潜力很重要。随后，PGCS然后增殖 分化为种系干细胞以产生配子。这些监管事件由 众所周知的信号是由躯体壁ches产生的。例如，哺乳动物PGC受到关键，但 来自生殖器山脊的未鉴定分化信号。我们对小众信号的不良理解 调节PGC的部分原因是模型系统的匮乏，在这种模型系统中，可以在其中可以进行利基-PGC相互作用 通过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强度来确定体细胞生态位 胚胎中的细胞调节PGC静止。许多基本和深刻的对生殖细胞的见解 生物学来自包括秀丽隐杆线虫在内的无脊椎动物模型的研究。胚胎包含两个PGC， 由两个体细胞细胞（SGP）包裹以形成原始性腺。 SGP充当利基市场 确保PGC保持静止，直到胚胎孵化为止。我们发现SGP在此实现这一目标 两种方式。首先，他们必须模板一个围绕原始的地下膜（BM） 性腺。其次，需要将它们传递出源自性腺BM的信号，以防止胚胎 PGC从退出静止。虽然信号的身份尚不清楚，但PGC静止的损失 当BM耗尽时发生，伴随着Notch信号通路的激活并被抑制 通过GLP-1 Notch受体中的突变。我们的中心假设是BM通过 抑制SGPS中的缺口配体，以防止其激活PGC中的GLP-1受体。具体 该建议的目标是确定SGP Notch配体以及BM蛋白和受体 调节PGC静止，并确定BM和Notch信号传导分量的接口。这些 基础研究将使我们能够将秀丽隐杆线虫性腺基原始人发展成一个强大的新模型 系统以研究对PGC的利基信号的分子基础。我们的发现将揭示特定的新 了解利基BM如何控制Notch信号以保持PGC静止，从而告知有关PGC静止 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 - 许多干细胞系统的关键调节剂。