Expression of FKHR, FKHRL1, and AFX Genes in the Rodent Ovary: Evidence for Regulation by IGF-I, Estrogen, and the Gonadotropins

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Abstract
Follicular development is dependent on both intra- ovarian growth regulatory factors, such as IGF-I and estrogen, as well as the pituitary gonadotropins, FSH and LH. Recently, we have shown that FSH impacts the IGF-I pathway via stimulation of the PI3K cascade leading to phosphorylation of protein kinase B (PKB)/ Akt and the PKB-related kinase, Sgk. This study was undertaken to determine if during ovarian follicular development FSH regulates putative targets of PKB and Sgk, namely specific Forkhead transcription fac- tor family members. Using in vivo and in vitro mouse and rat models, we show 1) that FKHR (Forkhead homolog of rhabdomysarcoma Forkhead box binding protein (Foxo1), FKHRL1 (Forkhead-like pro- tein-1 Foxo3), and AFX (a Forkhead transcription factor Foxo4); all defined according to the Human and Mouse Gene Nomenclature Committee) are expressed in the rodent ovary and 2) that FSH regu- lates transcription of the FKHR gene as well as phos- phorylation of FKHR protein. Specifically, FSH/PMSG (primarily via E2) enhance expression of the FKHR gene in granulosa cells of developing follicles. Fur- thermore, E2 enhances expression of other IGF-I pathway components (IGF-1R and Glut-1), and IGF-I enhances expression of ER, indicating that these two hormones comprise an autocrine regula- tory network within growing follicles. In contrast, FSH and LH/human CG (via cAMP, PKA, and PI3K pathways) terminate FKHR expression as granulosa cells differentiate to luteal cells. In naive granulosa cells, both FSH and IGF-I stimulate rapid phosphory- lation of FKHR at multiple sites causing its redistri- bution from the nucleus to the cytoplasm in a PI3K- dependent manner. However, the effects of FSH and IGF-I differ markedly in differentiated granu- losa cells in which FSH (but not IGF-I) induces Sgk and enhances phosphorylation of FKHR, PKB, and Sgk. The elevated expression of FKHR in granulosa cells of growing follicles indicates that FKHR may be linked to the proliferation of granulosa cells and that its phosphorylation by FSH, IGF-I, and other factors may impact its functional activity in this process. Thus, as a target of FSH (cAMP), E2 and IGF-I signaling in granulosa cells, FKHR likely co- ordinates numerous cell survival mechanisms. (Molecular Endocrinology 16: 580-599, 2002)

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