Molecular Mechanisms of FOXL2, An Ovarian Failure Gene

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DESCRIPTION (provided by applicant): Premature ovarian failure affects up to 1% of women by the age of 40. Although the etiology of premature ovarian failure remains largely unknown, a genetic basis has been determined for selective cases. Mutations in the gene encoding a forkhead transcription, Forkhead L2 (FOXL2) has been associated with this disorder. FOXL2 is present in the ovary and preliminary data reveals that it is localized to less differentiated granulosa cells of small and medium follicles and functions as a transcriptional represser of the Steroidogenic Acute Regulatory (StAR) gene, a marker of granulosa cell differentiation. Since FOXL2 may function as a represser of granulosa cell differentiation and steroidogenesis, we propose to evaluate FOXL2 transcriptional activity on other genes involved in the Steroidogenic cascade which contain putative forkhead consensus sites. Since FOXL2 may function as a represser of granulosa cell differentiation and hence steroidogenesis, we will evaluate steroid production in the granulosa cell following FOXL2 overexpression. In order to understand some of the underlying mechanism of FOXL2 regulation in the ovary, we performed a yeast two-hybrid screen using an ovarian fusion cDNA library to isolate FOXL2-interacting proteins. Large Tumor Suppressor Gene 1 (LATS1), a putative serine/threonine kinase and ovarian tumor suppressor gene, was identified to interact strongly with FOXL2. Mutations in LATS1, like mutations in FOXL2 produce a similar ovarian phenotype, premature ovarian failure. Thus, we propose that LATS1 and FOXL2 share a common pathway for follicular regulation. We will first localize LATS1 in the ovary, followed by defining the precise interaction between LATS1 and FOXL2. Since LATS1 is a serine/threonine kinase, and other forkhead family members are regulated by phosphorylation, we propose that FOXL2 transcriptional activity will be regulated by phosphorylation. Thus, we will also determine phosphorylation of FOXL2 by LATS1 and its regulation of transcriptional activity using our functional assay as well as through cellular localization. The proposed study could provide a better understanding of the mechanisms underlying premature ovarian failure.