A key point in germ cell development is the switch from stem/progenitor cells to meiosis and gametogenesis. Disruption of this developmental switch can result in infertility and in some cases germline tumors. The C. elegans adult hermaphrodite is an important model for understanding control of the switch from germline stem cell fate to meiotic development/gametogenesis, where a network controlling the process is emerging. Niche dependent GLP-1 Notch signaling promotes the stem cell fate through repressing three redundant posttranscriptional pathways that promote meiotic entry: the GLD-1 pathway (which represses expression of mitotic cycling genes), the GLD-2 pathway (which promotes expression of meiotic genes), and the SCFPROM-1 pathway that both degrades mitotic cell cycle proteins at meiotic entry and initiates homologous chromosome pairing. Current studies indicate that while transcriptional programs set the stage, it is largely posttranscriptional regulation that executes meiotic entry in animals. At a cellular level, we have shown that in C. elegans the stem cell population is large and germ cells enter meiosis directly, without intervening transit- amplifying divisions. The absence of transit-amplifying divisions simplifies the analysis allowing straightforward assays to identify genes involved in repressing meiosis in stem cells and repressing mitotic cell cycling at meiotic entry and is the primary reason why C. elegans is a major animal model for studying this important developmental switch. This proposal addresses three major gaps in knowledge and a major technical challenge in molecular/ biochemical mechanistic studies of the stem cell/progenitor switch to meiotic development in C. elegans. First, it is not known how SCFPROM-1 is repressed in stem/progenitor cells. Second, the mRNA targets of the GLD-1 translational repressor and the GLD-2 translational activator, which repress mitotic cycling and promote meiotic gene product accumulation, are largely unidentified. Third, mechanisms by which GLP-1 signaling is restricted to the stem cell niche region are not fully known, and the mechanism by which the mett-10 m6A methyltransferase inhibits GLP-1 signaling is undescribed. Molecular/biochemical studies of the switch from stem/progenitor cells to meiotic entry are limited by the C. elegans germline containing all stages, present in an assembly-line order from stem cells to mature gametes, with any given stage a small proportion. We will develop a genetic system for the synchronous switch from stem cells to meiotic entry, in a sufficiently large population of germ cells and animals to allow molecular/biochemical studies.
The proposed research investigates the stem cell versus differentiation decision, which is an essential part of animal development and adult tissue homeostasis. Disruption of the decision can cause premature stem cell differentiation, resulting in tissue dysfunction, including sterility, or can cause stem cell overproliferation, leading to cancer.
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