Fertility in females requires controlled maturation of the oocyte, supporting granulosa cells (GCs), and theca cells that comprise the ovarian follicle. Nutrients and hormones to support follicle maturation come from capillaries in the theca layer;vascularization terminates at the basement membrane. Thus, as follicles grow, GCs are exposed to increasingly hypoxic conditions. Follicle growth is a dynamic process that demands exquisite regulation. Follicles are restrained at the preantral stage until they are stimulated by the pituitary hormone follicle stimulating hormone (FSH). In response to FSH, GCs produce steroid and protein hormones and growth factors that regulate the hypothalamic/pituitary axis and uterine receptivity and promote oocyte maturation and development of the follicle to a preovulatory phenotype. We have shown that FSH promotes enhanced translation leading to an accumulation of the transcriptional factor hypoxia-inducible factor-1a (HIF1a) in GCs. HIF1a is normally absent under normoxia due to oxygen-dependent post-translational modifications that target it for proteosomal degradation, and accumulates only under hypoxic conditions. HIF1a, together with constitutively expressed HIF1b, form the heterodimeric transcriptional factor HIF1 that activates a hierarchy of target genes that permit cells to survive under reduced oxygen concentrations.
The aims of this application test the overarching hypothesis that proper GC function and follicular maturation require a HIF1-responsive transcriptome optimally regulated by FSH and hypoxia. Support for these aims comes from our evidence that FSH-stimulated HIF1 activity appears to be necessary for induction of a diverse group of target genes that include vascular endothelial growth factor (Vegf), inhibin-a (officially Inha), luteinizing hormone/choriogonadotropin receptor (officially Lhcgr), and protein kinase A regulatory subunit RIIb (officially Prkar2b). With the exception of Vegf, these apparent HIF1 targets in GCs are distinct from other common targets of this ubiquitous transcriptional activator. Thus, elucidation of the functional role of HIF1 is important not only to GC maturation and fertility but may also contribute to our understanding of the misregulation of genes such as the Lhcgr seen in many different cancer cells that express high levels of HIF1a. Moreover, understanding how FSH signals to direct follicular maturation can translate into safer and more effective treatments of infertility and early pregnancy loss as well as new approaches for contraceptive drugs.

Public Health Relevance

FSH signaling to mature follicles to the preovulatory phenotype is required for fertility. Understanding how FSH signals to direct follicular maturation can translate into safer and more effective treatments of infertility and early pregnancy loss as well as new approaches for contraceptive drugs.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
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Taymans, Susan
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Washington State University
Schools of Arts and Sciences
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Law, Nathan C; Donaubauer, Elyse M; Zeleznik, Anthony J et al. (2017) How Protein Kinase A Activates Canonical Tyrosine Kinase Signaling Pathways To Promote Granulosa Cell Differentiation. Endocrinology 158:2043-2051
Donaubauer, Elyse M; Law, Nathan C; Hunzicker-Dunn, Mary E (2016) Follicle-Stimulating Hormone (FSH)-dependent Regulation of Extracellular Regulated Kinase (ERK) Phosphorylation by the Mitogen-activated Protein (MAP) Kinase Phosphatase MKP3. J Biol Chem 291:19701-12
Puri, Pawan; Little-Ihrig, Lynda; Chandran, Uma et al. (2016) Protein Kinase A: A Master Kinase of Granulosa Cell Differentiation. Sci Rep 6:28132
Donaubauer, Elyse M; Hunzicker-Dunn, Mary E (2016) Extracellular Signal-regulated Kinase (ERK)-dependent Phosphorylation of Y-Box-binding Protein 1 (YB-1) Enhances Gene Expression in Granulosa Cells in Response to Follicle-stimulating Hormone (FSH). J Biol Chem 291:12145-60
Herndon, Maria K; Law, Nathan C; Donaubauer, Elyse M et al. (2016) Forkhead box O member FOXO1 regulates the majority of follicle-stimulating hormone responsive genes in ovarian granulosa cells. Mol Cell Endocrinol 434:116-26
Law, Nathan C; White, Morris F; Hunzicker-Dunn, Mary E (2016) G protein-coupled receptors (GPCRs) That Signal via Protein Kinase A (PKA) Cross-talk at Insulin Receptor Substrate 1 (IRS1) to Activate the phosphatidylinositol 3-kinase (PI3K)/AKT Pathway. J Biol Chem 291:27160-27169
Law, Nathan C; Hunzicker-Dunn, Mary E (2016) Insulin Receptor Substrate 1, the Hub Linking Follicle-stimulating Hormone to Phosphatidylinositol 3-Kinase Activation. J Biol Chem 291:4547-60