I The long-term objective of this proposal is to understand the underlying molecular basis of maternal mRNA translation in early mammalian development. Specific mRNAs encoding proteins such as cyclin B and mos are translationally activated in maturing mouse oocytes by the process of cytoplasmic polyadenylation. Polyadenylation in turn is controlled by short elements that reside in the 3'untranslated regions of the mRNAs, and by the proteins that interact with these elements. The key factor necessary for polyadenylation is CPEB. A knockout of the CPEB gene results in the cessation of oogenesis at pachytene and the prevention of synaptonemal complex formation. CPEB activity is dependent upon single site phosphorylation catalyzed by < urora, a protein kinase. We propose to investigate how Aurora is activated in mouse oocytes, and whether a phosphatase acts on phosphorylated CPEB to inactivate it at later times of oogenesis. We also propose to nvestigate cytoplasmic polyadenylation in the fertilized egg, and to determine the mRNAs that undergo this process at this time. We further propose to investigate the functions of two other CPEB-like proteins, at least one of which is present in oocytes as well as fertilized eggs. Finally, we propose to characterize maskin, a PEB-interacting factor that is key to linking polyadenylation to translational activation. With these proposed experiments, we will assess not only the mechanism of mammalian maternal mRNA is translation, but also will further investigate its clear importance for early development. Regulated mRNA translation is clearly important for the viability of all metazoans in which it has been examined. These proposed studies focus on early development, and consequently the results obtained will have ramifications for fertility and human development.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HD037267-14
Application #
8097358
Study Section
Special Emphasis Panel (NSS)
Program Officer
Ravindranath, Neelakanta
Project Start
1998-09-01
Project End
2012-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
14
Fiscal Year
2011
Total Cost
$329,212
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Genetics
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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Alexandrov, Ilya M; Ivshina, Maria; Jung, Dae Young et al. (2012) Cytoplasmic polyadenylation element binding protein deficiency stimulates PTEN and Stat3 mRNA translation and induces hepatic insulin resistance. PLoS Genet 8:e1002457
Nagaoka, Kentaro; Udagawa, Tsuyoshi; Richter, Joel D (2012) CPEB-mediated ZO-1 mRNA localization is required for epithelial tight-junction assembly and cell polarity. Nat Commun 3:675
Oruganty-Das, Aparna; Ng, Teclise; Udagawa, Tsuyoshi et al. (2012) Translational control of mitochondrial energy production mediates neuron morphogenesis. Cell Metab 16:789-800
Groppo, Rachel; Richter, Joel D (2011) CPEB control of NF-kappaB nuclear localization and interleukin-6 production mediates cellular senescence. Mol Cell Biol 31:2707-14
Burns, David M; D'Ambrogio, Andrea; Nottrott, Stephanie et al. (2011) CPEB and two poly(A) polymerases control miR-122 stability and p53 mRNA translation. Nature 473:105-8
Darnell, Jennifer C; Van Driesche, Sarah J; Zhang, Chaolin et al. (2011) FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146:247-61
Kan, Ming-Chung; Oruganty-Das, Aparna; Cooper-Morgan, Amalene et al. (2010) CPEB4 is a cell survival protein retained in the nucleus upon ischemia or endoplasmic reticulum calcium depletion. Mol Cell Biol 30:5658-71
Lin, Chien-Ling; Evans, Veronica; Shen, Shihao et al. (2010) The nuclear experience of CPEB: implications for RNA processing and translational control. RNA 16:338-48
Zearfoss, N Ruth; Alarcon, Juan Marcos; Trifilieff, Pierre et al. (2008) A molecular circuit composed of CPEB-1 and c-Jun controls growth hormone-mediated synaptic plasticity in the mouse hippocampus. J Neurosci 28:8502-9

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