The proposed research uses the genetic analysis of C. elegans to address two fundamental questions in germline development: how is the decision to either proliferate or enter the meiotic pathway executed? And how are meiotic prophase progression and gametogenesis controlled and coordinated? Disruption of these processes can result in germline tumor formation, sterility and aneuploid gemetes. We have identified mutations that cause germline tumorigenesis by two different mechanisms. Gain-of- function mutations in the glp-I and let-42 genes lead to tumorigenesis by preventing germline stem cells from exiting mitosis and entering the meiotic pathway. In contrast, loss-of- function mutations in the gld-I gene cause tumor formation by disrupting meiotic prophase progression and oogenesis. In animals lacking gld-1 activity, germ cells that would normally develop into oocytes enter and progress through meiotic prophase normally until the early pachytene stage, when they exit the meiotic pathway and return to a proliferative cell cycle. We have shown that this return to mitosis is dependent on the activity of MAP kinase. We have also identified a new gene, pex-2, that is important for meiotic prophase progression. glp-1, let-42 and gld-1 are evolutionarily conserved. GLP-1 is related to the Notch family of receptors, which includes the human TAN-1 proto-oncogene product. Let-42 shows similarity to an uncharacterized human cDNA. GLD-1, a putative RNA binding protein, shares homology with the mouse Quaking protein and the human Sam68 protein.
The specific aims of this proposal are to: A) identify genes that negatively regulate mitosis or positively regulate entry into meiosis by screening for enhancers of a weak glp-1 (gf) mutation; B) analyze the normal role of let-42 in germline proliferation; C) identify regulators, cofactors and RNA targets of GLD-1 and investigate the role of the MAP kinase pathway in germline tumorigenesis; and D) determine how pex-2 promotes meiotic prophase progression. The proposed studies relate to general aspects of biology and medicine. They will provide insights into: the regulation of mitosis; the control of entry into and progression through meiotic prophase; and the functioning and regulation of Notch family receptors, the MAP kinase signalling pathway, LET-42 and the GLD-1/Quaking/Sam68 subfamily of RNA binding proteins. This work may also provide new information about the cellular mechanisms that underlie human germline cancers.
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