The overall aim of this proposal is to better understand the regulation of gene expression during mammalian oocyte and early embryo development. Oocyte maturation is associated with suppression of transcription. Consequently, gene expression during oocyte maturation, fertilization, and early embryo development until zygotic genome activation (ZGA), is regulated by translational activation of maternally- stored mRNAs. Embryonic poly(A) binding protein (ePAB) is the predominant poly(A) binding protein during Xenopus, mouse and human oocyte and early embryo development until ZGA. In Xenopus, ePAB is required for both known pathways (cytoplasmic polyadenylation-dependent and independent) that mediate maternal mRNA translational activation upon oocyte maturation. In addition, our preliminary findings demonstrate that oocyte maturation is inhibited when ePAB activity is suppressed in Xenopus oocytes, and that ePAB-deficient female mice are infertile due to impaired oogenesis. We therefore hypothesize that ePAB plays a key role in the regulation of gene expression during a critical period of early development, when transcription is suppressed. Here, we propose to characterize the cellular and molecular aspects of infertility in ePAB-deficient mice and to determine regulation of ePAB's function by phosphorylation.
The specific aims of this proposal are to: 1. Determine ePAB-null phenotype using a knockout mouse model. 2. Determine the role of ePAB phosphorylation in the regulation of maternal mRNA translational activation and oocyte maturation. These proposed studies focus on early development, and consequently the results obtained will have ramifications for human development and fertility.

Public Health Relevance

The overall aim of this proposal is to better understand the regulation of gene expression during mammalian egg and early embryo development. Our ultimate goal is to characterize the molecular mechanisms responsible for important reproductive problems such as oocyte aging, and embryo loss. As a result of this enhanced understanding, development of targeted therapeutic strategies can ensue.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD059909-03
Application #
8392185
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Ravindranath, Neelakanta
Project Start
2010-12-21
Project End
2015-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
3
Fiscal Year
2013
Total Cost
$335,180
Indirect Cost
$133,517
Name
Yale University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Yang, Cai-Rong; Lowther, Katie M; Lalioti, Maria D et al. (2016) Embryonic Poly(A)-Binding Protein (EPAB) Is Required for Granulosa Cell EGF Signaling and Cumulus Expansion in Female Mice. Endocrinology 157:405-16
Babayev, Elnur; Lalioti, Maria D; Favero, Federico et al. (2016) Cross-Talk Between FSH and Endoplasmic Reticulum Stress: A Mutually Suppressive Relationship. Reprod Sci 23:352-64
Lowther, Katie M; Mehlmann, Lisa M (2015) Embryonic Poly(A)-Binding Protein Is Required During Early Stages of Mouse Oocyte Development for Chromatin Organization, Transcriptional Silencing, and Meiotic Competence. Biol Reprod 93:43
Ata, Baris; Seli, Emre (2015) Strategies for Controlled Ovarian Stimulation in the Setting of Ovarian Aging. Semin Reprod Med 33:436-48
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Babayev, Elnur; Seli, Emre (2015) Oocyte mitochondrial function and reproduction. Curr Opin Obstet Gynecol 27:175-81
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Karakaya, Cengiz; Guzeloglu-Kayisli, Ozlem; Hobbs, Rebecca J et al. (2014) Follicle-stimulating hormone receptor (FSHR) alternative skipping of exon 2 or 3 affects ovarian response to FSH. Mol Hum Reprod 20:630-43
Karalok, Hakan Mete; Aydin, Ebru; Saglam, Ozlen et al. (2014) mRNA-binding protein TIA-1 reduces cytokine expression in human endometrial stromal cells and is down-regulated in ectopic endometrium. J Clin Endocrinol Metab 99:E2610-9

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