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

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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.