The long-term goal of the studies proposed in this application is to define the role of regulated mRNA translation in the control of oocyte cell cycle progression. Meiotic cell cycle progression during vertebrate oocyte maturation is controlled by proteins that are translated from maternally derived mRNAs. In the model system, Xenopus laevis, translational induction of dormant mRNAs encoding cell cycle control proteins must occur in a strict temporal order. Translationally induced maternal mRNAs can be classified based on their temporal activation into early and late class mRNAs following progesterone stimulation. The induction of maternal mRNA translation is directed through regulatory elements in the mRNA 3'untranslated regions that are targeted by sequence-specific RNA binding proteins. We have recently made the seminal finding that the RNA binding protein, Musashi, is the critical temporal determinant of early class mRNA translational induction during Xenopus oocyte maturation. Although Musashi has been implicated in mRNA translational control during neural and epithelial stem cell self renewal, the mechanism by which Musashi regulates mRNA translation is unknown. In the studies proposed in this application, we will test the hypothesis that Musashi-mediated mRNA translational control is a key regulator of cell cycle progression in vertebrate oocytes. Specifically, we will elucidate the mechanisms by which Musashi regulates mRNA translational activation during Xenopus oocyte maturation and determine how Musashi discriminates early class target mRNAs. The experiments described in this proposal will address several key issues regarding the mechanisms of maternal mRNA translational control. We will elucidate the initiating progesterone- dependent regulatory events that impinge on early class mRNA translation. We will determine if Musashi interacts with consensus as well as non-consensus binding sites in the target mRNA 3'UTRs. We will elucidate the relationship of Musashi to the coordination and control of Mos and Ringo mRNA translation and we will test the hypothesis that Musashi-mediated early class mRNA translation is essential for CPE- dependent late class mRNA translation. The insights derived from the study of Musashi function during oocyte maturation will enhance our understanding of this key aspect of reproductive biology.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD035688-12
Application #
8113462
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Ravindranath, Neelakanta
Project Start
1998-12-15
Project End
2014-06-30
Budget Start
2011-07-01
Budget End
2014-06-30
Support Year
12
Fiscal Year
2011
Total Cost
$250,111
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
MacNicol, Melanie C; Cragle, Chad E; McDaniel, F Kennedy et al. (2017) Evasion of regulatory phosphorylation by an alternatively spliced isoform of Musashi2. Sci Rep 7:11503
MacNicol, Melanie C; Cragle, Chad E; Arumugam, Karthik et al. (2015) Functional Integration of mRNA Translational Control Programs. Biomolecules 5:1580-99
MacNicol, Angus M; Hardy, Linda L; Spencer, Horace J et al. (2015) Neural stem and progenitor cell fate transition requires regulation of Musashi1 function. BMC Dev Biol 15:15
Janganati, Venumadhav; Penthala, Narsimha Reddy; Cragle, Chad E et al. (2014) Heterocyclic aminoparthenolide derivatives modulate G(2)-M cell cycle progression during Xenopus oocyte maturation. Bioorg Med Chem Lett 24:1963-7
Cragle, Chad; MacNicol, Angus M (2014) Musashi protein-directed translational activation of target mRNAs is mediated by the poly(A) polymerase, germ line development defective-2. J Biol Chem 289:14239-51
Rutledge, Charlotte E; Lau, Ho-Tak; Mangan, Hazel et al. (2014) Efficient translation of Dnmt1 requires cytoplasmic polyadenylation and Musashi binding elements. PLoS One 9:e88385
Penthala, Narsimha R; Bommagani, Shobanbabu; Janganati, Venumadhav et al. (2014) Heck products of parthenolide and melampomagnolide-B as anticancer modulators that modify cell cycle progression. Eur J Med Chem 85:517-25
Arumugam, Karthik; MacNicol, Melanie C; Wang, Yiying et al. (2012) Ringo/cyclin-dependent kinase and mitogen-activated protein kinase signaling pathways regulate the activity of the cell fate determinant Musashi to promote cell cycle re-entry in Xenopus oocytes. J Biol Chem 287:10639-49
Arumugam, Karthik; Macnicol, Melanie C; Macnicol, Angus M (2012) Autoregulation of Musashi1 mRNA translation during Xenopus oocyte maturation. Mol Reprod Dev 79:553-63
Charlesworth, Amanda; Yamamoto, Tomomi M; Cook, Jonathan M et al. (2012) Xenopus laevis zygote arrest 2 (zar2) encodes a zinc finger RNA-binding protein that binds to the translational control sequence in the maternal Wee1 mRNA and regulates translation. Dev Biol 369:177-90

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