Our objective is to define the mechanisms by which intercellular signaling coordinates meiosis and fertilization in the nematode C. elegans. 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. Our research established C. elegans as a genetic paradigm for studying hormonal control of meiotic maturation. C. elegans sperm export the major sperm protein (MSP) hormone to trigger meiotic maturation. A major advance in the prior award period was our finding that G1s-adenylate cyclase signaling in the follicle-like sheath cells is required for all known MSP-dependent meiotic maturation responses in the germline. By contrast, the VAB-1 MSP/Eph receptor plays a non-essential role in the oocyte to inhibit meiotic maturation when MSP is absent.
The Specific Aims of this application test a model for the somatic control of meiotic maturation in which the sheath cells control the oocyte response.
AIM 1 defines how the sheath cells receive the MSP signal. We will test the hypothesis that MSP binds multiple G protein-coupled receptors (GPCRs) to promote meiotic maturation. FRET measurements will ask whether MSP activates the G1s-adenylate cyclase pathway in sheath cells. A series of functional tests will examine the role of sheath cell-expressed GPCRs in meiotic maturation. Conserved MSP-binding GPCRs may mediate the signaling of MSP-related ligands in mammals.
AIM 2 elucidates how the sheath cells transduce the MSP signal to the oocyte. We will test the hypothesis that somatic cAMP-dependent protein kinase A promotes meiotic maturation by antagonizing two inhibitory pathways. Genetic tests will address whether PKA is required in the sheath cells for meiotic maturation and whether individual acy-4 suppressor loci function downstream of PKA. We will molecularly identify critical suppressor loci. These lines of investigation will define how the sheath cells communicate the presence of MSP to the oocyte.
AIM 3 dissects translational control mechanisms required for meiotic maturation. The conserved zinc finger proteins OMA-1 and OMA-2 (OMA proteins) are redundantly required for meiotic maturation. Proteomic analyses suggest that OMA proteins function as post-transcriptional gene regulators. We will test the hypothesis that OMA proteins function to repress translation of meiotic maturation factor mRNAs when MSP is absent, but activate translation when MSP is present. We will first identify mRNAs in OMA- ribonucleoproteins using RNA-binding protein immunoprecipitation-microarray profiling. We will then determine the effects of OMA proteins, MSP signaling, and OMA-ribonucleoprotein components on expression of key target mRNAs. These studies will provide insights into translational regulation of meiotic maturation.
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. The small roundworm C. elegans is an established model for studying the hormonal control of meiosis. These studies will define the signaling mechanisms controlling female meiosis and provide insights into the origin of meiotic errors.
|Spike, Caroline A; Coetzee, Donna; Nishi, Yuichi et al. (2014) Translational control of the oogenic program by components of OMA ribonucleoprotein particles in Caenorhabditis elegans. Genetics 198:1513-33|
|Starich, Todd A; Hall, David H; Greenstein, David (2014) Two classes of gap junction channels mediate soma-germline interactions essential for germline proliferation and gametogenesis in Caenorhabditis elegans. Genetics 198:1127-53|
|Spike, Caroline A; Coetzee, Donna; Eichten, Carly et al. (2014) The TRIM-NHL protein LIN-41 and the OMA RNA-binding proteins antagonistically control the prophase-to-metaphase transition and growth of Caenorhabditis elegans oocytes. Genetics 198:1535-58|
|Kim, Seongseop; Spike, Caroline; Greenstein, David (2013) Control of oocyte growth and meiotic maturation in Caenorhabditis elegans. Adv Exp Med Biol 757:277-320|
|Oldenbroek, Marieke; Robertson, Scott M; Guven-Ozkan, Tugba et al. (2013) Regulation of maternal Wnt mRNA translation in C. elegans embryos. Development 140:4614-23|
|Rao, Meghana; Song, Wenqiang; Jiang, Aixiang et al. (2012) VAMP-associated protein B (VAPB) promotes breast tumor growth by modulation of Akt activity. PLoS One 7:e46281|
|Kim, Seongseop; Govindan, J Amaranath; Tu, Zheng Jin et al. (2012) SACY-1 DEAD-Box helicase links the somatic control of oocyte meiotic maturation to the sperm-to-oocyte switch and gamete maintenance in Caenorhabditis elegans. Genetics 192:905-28|
|Ernstrom, Glen G; Weimer, Robby; Pawar, Divya R L et al. (2012) V-ATPase V1 sector is required for corpse clearance and neurotransmission in Caenorhabditis elegans. Genetics 191:461-75|
|Govindan, J Amaranath; Nadarajan, Saravanapriah; Kim, Seongseop et al. (2009) Somatic cAMP signaling regulates MSP-dependent oocyte growth and meiotic maturation in C. elegans. Development 136:2211-21|
|Nadarajan, Saravanapriah; Govindan, J Amaranath; McGovern, Marie et al. (2009) MSP and GLP-1/Notch signaling coordinately regulate actomyosin-dependent cytoplasmic streaming and oocyte growth in C. elegans. Development 136:2223-34|
Showing the most recent 10 out of 17 publications