The coordination of oocyte and follicular development are essential for the development of oocytes, oocyte maturation, and timely ovulation in a condition optimal for fertilization subsequent embryogenesis.
The Specific Aims of this application are focused on mechanisms by which oocyte-derived paracrine factors interact with hormonal stimuli to coordinate oocyte and follicular development and define the molecular and functional architecture of antral follicles. By doing so, oocytes establish the functional compartmentalization of antral follicles that is essential for cumulus cell support of oocyte development, the oocyte-granulosa cell regulatory loop, and mural granulosa cell endocrine function.
In Aim 1, the hypothesis that the oocyte-derived paracrine factors bone morphogenetic protein 15 (BMP15), growth differentiation factor 9 (GDF9), and fibroblast growth factor 8 (FGF8) are positive regulators of the rate of follicular development and that oocyte-derived bone morphogenetic protein 6 (BMP6) is a negative regulator will be tested. Genetic models and culture systems will be used to test this hypothesis. Particular emphasis will be placed on oocyte- regulation of granulosa cell glycolysis and cholesterol biosynthesis as means to control the rate of follicular development.
In Aim 2, the hypothesis that oocytes control follicular development by affecting how granulosa cells respond to hormonal stimuli will be tested. The regulation of follicular development is complex, involving gonadotropins, steroid hormones, and other paracrine and autocrine growth factors that are crucially important for controlling granulosa cell proliferation and differentiation. Initial studies in this Aim will focus on the interactions of oocyte-derived paracrine factors with functions of FSH.
In Aim 3, the hypothesis that oocytes establish the molecular and functional architecture of follicular granulosa cell compartments in antral follicles will be tested. It is postulated that oocytes in their final growth phase trigger the differentiation of a subset of preantral granulosa cells to cumulus cells. Furthermore, in the absence of oocytes, FSH drives the differentiation of preantral granulosa cells to mural granulosa cells, which is, therefore, the "default" pathway of granulosa cell development. These experiments will therefore define the role of oocytes and FSH in establishing the molecular and functional architecture of antral follicles. In sum, this application addresses the role of oocytes in controlling the rate of ovarian follicular development and the organization of its granulosa cell components.Relevance to Public Health Infertility affects roughly 15% of couples and about 50% of these are attributable to female conditions. Although the etiologies causing female infertility are diverse, poor development of oocytes and follicles, ovulatory failure, and premature menopause are prominent among them. Coordination of the development of oocytes, the female germ cells, with the non-germ cell, or somatic, components of ovarian follicles are essential for fertility and the production of healthy offspring. This research program focuses on how oocytes interact with hormones to control the rate of follicular development and function of somatic cells that surround them in the follicle. This is important because defects in these control mechanisms negatively affect follicular development, ovulation, egg quality and development. Resolution of these mechanisms of intercellular signaling will lead to novel clinical solutions to female infertility.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD023839-23
Application #
8309808
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Taymans, Susan
Project Start
1988-02-03
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
23
Fiscal Year
2012
Total Cost
$345,322
Indirect Cost
$145,714
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Dokshin, Gregoriy A; Baltus, Andrew E; Eppig, John J et al. (2013) Oocyte differentiation is genetically dissociable from meiosis in mice. Nat Genet 45:877-83
Lee, Kyung-Bon; Zhang, Meijia; Sugiura, Koji et al. (2013) Hormonal coordination of natriuretic peptide type C and natriuretic peptide receptor 3 expression in mouse granulosa cells. Biol Reprod 88:42
Peng, Jia; Li, Qinglei; Wigglesworth, Karen et al. (2013) Growth differentiation factor 9:bone morphogenetic protein 15 heterodimers are potent regulators of ovarian functions. Proc Natl Acad Sci U S A 110:E776-85
Wigglesworth, Karen; Lee, Kyung-Bon; O'Brien, Marilyn J et al. (2013) Bidirectional communication between oocytes and ovarian follicular somatic cells is required for meiotic arrest of mammalian oocytes. Proc Natl Acad Sci U S A 110:E3723-9
Zhang, Meijia; Su, You-Qiang; Sugiura, Koji et al. (2011) Estradiol promotes and maintains cumulus cell expression of natriuretic peptide receptor 2 (NPR2) and meiotic arrest in mouse oocytes in vitro. Endocrinology 152:4377-85
Su, You-Qiang; Sugiura, Koji; Li, Qinglei et al. (2010) Mouse oocytes enable LH-induced maturation of the cumulus-oocyte complex via promoting EGF receptor-dependent signaling. Mol Endocrinol 24:1230-9
Zhang, Meijia; Su, You-Qiang; Sugiura, Koji et al. (2010) Granulosa cell ligand NPPC and its receptor NPR2 maintain meiotic arrest in mouse oocytes. Science 330:366-9
Tian, X; Halfhill, A N; Diaz, F J (2010) Localization of phosphorylated SMAD proteins in granulosa cells, oocytes and oviduct of female mice. Gene Expr Patterns 10:105-12
Sugiura, Koji; Su, You-Qiang; Li, Qinglei et al. (2009) Fibroblast growth factors and epidermal growth factor cooperate with oocyte-derived members of the TGFbeta superfamily to regulate Spry2 mRNA levels in mouse cumulus cells. Biol Reprod 81:833-41
Su, You-Qiang; Sugiura, Koji; Eppig, John J (2009) Mouse oocyte control of granulosa cell development and function: paracrine regulation of cumulus cell metabolism. Semin Reprod Med 27:32-42

Showing the most recent 10 out of 46 publications