FSH signaling pathways in immature granulosa cells that regulate target gene expression: branching out from protein kinase A

Abstract

Follicle-stimulating hormone (FSH) is necessary and sufficient to induce maturation of ovarian follicles to a mature, preovulatory phenotype in the intact animal, resulting in the generation of mature eggs and production of estrogen. FSH accomplishes these actions by inducing a complex pattern of gene expression in target granulosa cells that is regulated by input from many different signaling cascades, including those for the extracellular regulated kinases (ERKs), p38 mitogen-activated protein kinases (MAPKs), and phosphatidylinositol-3 kinase (PI3K). The upstream kinase that appears to be responsible for initiating all of the signaling that regulates gene expression in these epithelial cells is protein kinase A (PKA). PKA not only signals to directly phosphorylate transcription factors like cAMP response element binding protein and to promote chromatin remodeling by phosphorylating histone H3, this versatile kinase also enhances the activity of the p38 MAPK, ERK, and PI3K pathways. Additionally, accumulating evidence suggests that activation of a single signaling cascade downstream of PKA is not sufficient to activate target gene expression. Rather, cross-talk between and among signaling cascades is required. We will review the signaling cascades activated by FSH in granulosa cells and how these cascades contribute to the regulation of select target gene expression.

Fig. 1

FSH activates a complex program to promote of gene expression differentiation and proliferation of granulosa cells to achieve formation of the preovulatory follicle. This figure is a schematic diagram showing a subset of the FSH-regulated differentiation targets. In primary culture of rat granulosa cells, activin plus FSH are required to achieve initiation of the cell cycle.

Fig. 2

FSH-regulated signaling pathways in granulosa cells. This figure is a schematic diagram of our current understanding of signaling pathways utilized by FSH to regulate target gene expression in estrogen-treated granulosa cells.