Tissues are formed and maintained by stem cells that produce both daughters that undergo self-renewing proliferation and daughters that differentiate. The mechanisms by which the choice between proliferation and differentiation are made are not well understood in any system. Our long-term goal is to understand how the proliferation vs. differentiation decision is made in the C. elegans germline. The GLP-1 /Notch signaling pathway induces germ cells to proliferate while GLD-1, a conserved translational represser RNA binding protein, is a key downstream differentiation factor that promotes meiotic development. Spatial control of both GLP-1/Notch signaling and GLD-1 accumulation determines the correct balance between proliferation and meiotic development in C. elegans. Notch signaling in mammals is also important in stem cell self-renewal and oncogenic Notch activation can lead to cancer. The goal of Aim 1 is to identify and characterize negative regulators of GLP-1/Notch signaling that function to limit the size of the proliferative germ cell population. Mechanisms by which Notch signaling is down-regulated are not well understood but are of general importance since there are a number of developmental contexts where activated Notch proteins must be cleared between successive rounds of Notch mediated cell fate specification (e.g. nervous system).
Aim 2 employs cell biological approaches to understand how GLP-1/Notch signaling controls proliferation over a distance of 20 cell diameters. The rise in GLD-1 levels, which is regulated by both translational activators and repressors, determines where germ cells enter meiosis and in Aim 3, additional gene products necessary for this control will be identified and characterized.
In Aim 4, mRNA targets of GLD-1 that mediate initiation of meiotic development will be identified and characterized. GLD-1 likely translationally represses these RNAs to promote meiotic development. Since little is known about activities that lead to entry into meiotic prophase in animals, results from this aim will provide an initial picture.
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