Monday, April 29, 2024
4/29/2024
Project Summary/Abstract A key step in animal germ cell development is the switch in fate from stem/progenitor cells to entering meiotic prophase en route to gametogenesis. Disruption of this switch results in infertility and/or aneuploidy. Conserved features of the developmental transition include stem cell self-renewal followed by initiation of the meiotic program (e.g., homologous chromosome pairing, synapsis, double strand break formation) and repression of mitotic cell cycling. Multiple pathways function in control of the switch, resulting in genetic redundancy that has impeded the identification of key regulators. Furthermore, the regulatory process is heavily reliant on posttranscriptional control mechanisms. Studies of this switch in animals have progressed farthest in C. elegans. This is in part because the developmental transitions follow a convenient spatial continuum, allowing facile analysis of changes in cellular state (e.g. levels of regulators, changes in chromosome behavior) in wild type and mutant backgrounds. We have identified three parallel redundant pathways that control the switch in C. elegans. Yet, important questions remain. How is the switch spatially controlled? Here we focus on one of the pathways, the SCFPROM-1 pathway, an E3 ubiquitin ligase that functions in protein degradation. SCFPROM-1 induces meiotic entry and inhibits mitotic cell cycling, and its activity is controlled by PROM-1 proteins levels that rise from a base in stem cells to a peak at meiotic entry. Proposed studies of the spatial control will uncover how the activity and function of SCFPROM-1 is regulated and is coordinated with the other two known pathways, how meiotic entry is repressed in stem cells, and how mitotic cell cycling is repressed at meiotic entry. What are the missing regulators that execute the switch? The regulatory network contains significant genetic redundancy and there is evidence for missing regulators. Leveraging a novel in vivo genetic system we developed to synchronously switch stem cells to meiotic entry, we are employing genome-wide integrated transcriptomics, translatomics and proteomics, followed by genetic functional analysis to identify missing regulators. This combined genomics and genetically targeted functional analysis will overcome genetic redundancy in the developmental switch, which is difficult in less tractable organisms. Our overall goal is to complete the regulatory network and delineate processes governing an essential step in germline development, which will inform studies in other animals. Our investigations will uncover new developmental, cellular and molecular principles that are important for human health. This fundamental basic research in a genetic model organism will produce foundational knowledge for understanding cell fate switches, as well as the origin of birth defects and fertility.
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