In sexually reproducing animals, oocytes arrest at diplotene or diakinesis and resume meiosis (meiotic maturation) in response to hormones. Chromosome segregation errors in female meiosis I are the leading cause of human birth defects, and age-related changes in the hormonal environment of the ovary are a suggested cause. Caenorhabditis elegans is emerging as a genetic system for studying hormonal control of meiotic maturation. The meiotic maturation processes in C. elegans and mammals share a number of biological and molecular similarities. Major sperm protein (MSP) and luteinizing hormone (LH), though unrelated in sequence, both trigger meiotic resumption using somatic Gαadenylate cyclase pathways and soma-germline gap-junctional communication. I used C. elegans as a model for studying the genetic control of oocyte meiotic maturation. I conducted a forward genetic screen to identify new regulators of meiotic maturation that function downstream of somatic Gαadenylate cyclase signaling. I screened for mutations that suppress the meiotic maturation defect caused by defective Gαadenylate cyclase signaling and identified ten Sacy of underline acy underline-4 sterility) genetic loci, including sacy-1, which encodes a highly conserved DEAD-box helicase. SACY-1 appears to be a multifunctional protein that establishes a mechanistic link connecting the somatic control of meiotic maturation to germline sex determination, gamete maintenance, and post-transcriptional gene regulation in the germ line. To identify the molecular mechanisms by which sacy-1 functions in multiple germline developmental pathways, I conducted a genome-wide RNAi screen for genetic loci that enhance a hypomorphic sacy-1 mutant allele upon their depletion. This RNAi enhancer screen revealed multiple spliceosomal C complex proteins as genetic interactors of sacy-1. This result suggests several potential models for future work. One possibility is that sacy-1 might function as a spliceosomal component to regulate specific splicing events needed for execution of multiple germline developmental events. Alternatively, sacy-1, together with a subset of spliceosomal C complex components, might regulate downstream protein-RNA transactions important for germline development. While my work provides insights gained from a genetic analysis of meiotic maturation signaling in C. elegans, the conserved factors identified here might inform analysis in other systems through either homology or analogy.
University of Minnesota Ph.D. dissertation. May 2013. Major: Molecular, Cellular, Developmental Biology and Genetics. Advisor: David I. Greenstein. 1 computer file (PDF); ix, 238 pages.
On the genetic control of oocyte meiotic maturation in Caenorhabditis elegans.
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