The long-term objective of this project is to identify and characterize the molecular mechanisms that control the onset of meiosis during germline development. Meiosis occurs in the germ cells of every sexually reproducing organism; improper regulation of meiosis in humans can lead to reproductive dysfunction. This proposal focuses on the molecular mechanisms that regulate meiotic entry in the C. elegans germ line, a system amenable to genetic and molecular analyses. Previous work of others has shown that the GLP-1 receptor, a member of the conserved LIN-12/Notch family of intercellular receptors, is central to the mitosis/meiosis decision. Alteration of LIN-12/Notch-mediated signaling has been implicated in human disease. In C. elegans, activation of the GLP-1 receptor in the distal germ line establishes a germline stem-cell population. During development, GLP-1 must be down-regulated at the opposite end of the gonad arm, the proximal germ line, to ensure that meiotic entry occurs in the proximal-most position - otherwise sterility results. The mechanisms that govern GLP-1 activity in the proximal germ line, and thus control meiotic entry, are unknown. Mutants that display a proximal proliferation"""""""" (Pro) phenotype offer a unique tool to study the proximal regulation of GLP-1-mediated signaling and its influence on the onset of meiosis. The Pro phenotype is a specific spatial rearrangement of germline polarity characterized by inappropriate mitosis of proximal germ cells, without affecting the mitosis/meiosis decision of cells emanating from the stem-cell population in the distal germ line.
The specific aims of the proposal are threefold. First, four new Pro mutants will be genetically and phenotypically characterized, and more Pro mutants will be obtained. Second, a complete genetic, phenotypic and molecular characterization of one of the new Pro genes will be undertaken. Third, cell ablation techniques will be used to determine whether regulation of the timing of meiosis depends on signaling' from the proximal somatic gonad.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Study Section
Reproductive Biology Study Section (REB)
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Greenberg, Judith H
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New York University
Schools of Arts and Sciences
New York
United States
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Roy, Debasmita; Kahler, David J; Yun, Chi et al. (2018) Functional Interactions Between rsks-1/S6K, glp-1/Notch, and Regulators of Caenorhabditis elegans Fertility and Germline Stem Cell Maintenance. G3 (Bethesda) 8:3293-3309
McGovern, Marie; Castaneda, Perla Gisela; Pekar, Olga et al. (2018) The DSL ligand APX-1 is required for normal ovulation in C. elegans. Dev Biol 435:162-169
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Roy, Debasmita; Michaelson, David; Hochman, Tsivia et al. (2016) Cell cycle features of C. elegans germline stem/progenitor cells vary temporally and spatially. Dev Biol 409:261-271
Atwell, Kathryn; Qin, Zhao; Gavaghan, David et al. (2015) Mechano-logical model of C. elegans germ line suggests feedback on the cell cycle. Development 142:3902-11
Deng, Xinzhu; Michaelson, David; Tchieu, Jason et al. (2015) Targeting Homologous Recombination in Notch-Driven C. elegans Stem Cell and Human Tumors. PLoS One 10:e0127862
Qin, Zhao; Hubbard, E Jane Albert (2015) Non-autonomous DAF-16/FOXO activity antagonizes age-related loss of C. elegans germline stem/progenitor cells. Nat Commun 6:7107
Hubbard, E Jane Albert (2014) FLP/FRT and Cre/lox recombination technology in C. elegans. Methods 68:417-24
Hubbard, E Jane Albert; Korta, Dorota Z; Dalfó, Diana (2013) Physiological control of germline development. Adv Exp Med Biol 757:101-31

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