Defects in oocyte meiotic maturation are a major cause of human birth defects, miscarriage, and infertility. Many of the defining cellular, molecular, and biochemical features of meiotic maturation are deeply conserved. Over two decades, our research team established the nematode Caenorhabditis elegans as a genetic model for studying the control of meiotic maturation by intercellular signaling. In C. elegans, sperm signaling, via the major sperm protein (MSP), soma-germline interactions, and spatial cues regulate meiotic maturation. These signals ultimately result in the activation of maturation-promoting factor, the key regulator of meiotic maturation in most or all animals, which consists of the CDK1 protein kinase and the cyclin B regulatory subunit. Because late stage oocytes of most animals are transcriptionally quiescent, the regulation of protein translation is a key control point not only for meiotic maturation but also for additional aspects of oocyte development. In the prior funding period, we defined the central translational regulatory ribonucleoprotein (RNP) machine controlling meiotic maturation, which contains the conserved RNA-binding proteins (RBPs) LIN-41 and OMA-1/2 (referred to as the OMA proteins). LIN-41 and the OMA proteins act both in concert and antagonistically: LIN-41 inhibits CDK-1 activation and promotes oocyte growth and is inactivated in a spatially restricted manner to enable meiotic maturation, whereas the OMA proteins are required for CDK- 1 activation and meiotic maturation. We conducted extensive proteomic and genomic analyses to define additional protein components of the RNP machine and its mRNA targets. LIN-41?OMA RNP complexes not only arbitrate the spatial restriction of meiotic maturation, but they coordinate this key decision with oocyte growth and differentiation by controlling the translation of hundreds of important oogenic genes. The central questions are: (1) how LIN-41?OMA RNP complexes act as a switch to control meiotic maturation; and (2) how posttranslational mechanisms regulate the activity of LIN-41 to temporally and spatially control meiotic maturation and ensure its fidelity. Importantly, in mammals an OMA paralog is required for normal meiotic maturation, suggesting what we learn in C. elegans will provide general insights.
Aim 1 will identify the molecular mechanisms and pathways LIN-41 and the OMA proteins regulate to control meiotic maturation. To achieve this goal we will: define the mechanism by which the OMA proteins control a translational repression- to-activation switch; and determine the mechanisms by which the RNPs remodel the oocyte proteome for meiotic maturation and the oocyte-to-embryo transition.
Aim 2 will delineate the mechanisms by which LIN-41 is regulated to control meiotic maturation. To accomplish this goal, we will: determine how LIN-41 degradation might function as a timer to ensure the fidelity of the meiotic divisions; and illuminate the mechanism that inactivates LIN-41 as a translational repressor prior to its degradation. This basic research will broadly instruct our understanding of oogenesis and translational control.

Public Health Relevance

Defects in oocyte growth and the completion of meiosis (meiotic maturation) represent a major cause of human birth defects, miscarriage and infertility. Because ethical and technical issues limit the mechanistic depth of data obtained from human studies, model systems are invaluable for understanding the cellular events of female meiosis and their control. This application will delineate essential conserved mechanisms by which intercellular signaling and translational regulation coordinately control oocyte growth and meiotic maturation in the nematode Caenorhabditis elegans.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM057173-19
Application #
10006832
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Salazar, Desiree Lynn
Project Start
1998-05-01
Project End
2023-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
19
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Genetics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Spike, Caroline A; Huelgas-Morales, Gabriela; Tsukamoto, Tatsuya et al. (2018) Multiple Mechanisms Inactivate the LIN-41 RNA-Binding Protein To Ensure a Robust Oocyte-to-Embryo Transition in Caenorhabditis elegans. Genetics 210:1011-1037
Huelgas Morales, Gabriela; Greenstein, David (2018) C. elegans germline cell death, live! PLoS Genet 14:e1007425
Huelgas-Morales, Gabriela; Greenstein, David (2018) Control of oocyte meiotic maturation in C. elegans. Semin Cell Dev Biol 84:90-99
Tsukamoto, Tatsuya; Gearhart, Micah D; Spike, Caroline A et al. (2017) LIN-41 and OMA Ribonucleoprotein Complexes Mediate a Translational Repression-to-Activation Switch Controlling Oocyte Meiotic Maturation and the Oocyte-to-Embryo Transition in Caenorhabditis elegans. Genetics 206:2007-2039
Huelgas-Morales, Gabriela; Silva-GarcĂ­a, Carlos Giovanni; Salinas, Laura S et al. (2016) The Stress Granule RNA-Binding Protein TIAR-1 Protects Female Germ Cells from Heat Shock in Caenorhabditis elegans. G3 (Bethesda) 6:1031-47
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
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; Nishi, Yuichi et al. (2014) Translational control of the oogenic program by components of OMA ribonucleoprotein particles in Caenorhabditis elegans. Genetics 198:1513-33
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

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