Grant: Project Grant

Follicle-stimulating hormone (FSH) is produced in the pituitary gland, which sits at the base of the brain. It is one of two pituitary hormones that regulate gonadal function and reproductive physiology. FSH stimulates ovarian follicles to grow, a pre-requisite for ovulation. In males, FSH stimulates sperm production. FSH is used to treat infertile women and men. The production and secretion of FSH depends on gonadotropin-releasing hormone from the brain and, as we recently discovered, a hormone from the muscle called myostatin. Another hormone similar to myostatin, growth differentiation factor 11 (GDF11), also stimulates FSH production but the tissue in which it is produced has not been established. In mice, myostatin/GDF11 stimulate FSH production by increasing the activity (transcription) of the gene that encodes one of its constituent subunits, so-called FSHß. Regions of genes called promoters provide the DNA template through which proteins called transcription factors can activate genes. Myostatin/GDF11 stimulate the binding of specific transcription factors to the FSHß promoter in mice. In addition to promoters, additional regions of DNA called enhancers can further regulate gene activity. We recently identified four candidate enhancer regions for FSHß in mice, two of which also occur in humans. One of these latter regions contains genetic variants associated with differences in circulating FSH levels in women. The goals of this project grant are to determine: 1) whether the GDF11 regulating FSH comes from the brain, 2) the relative roles of the candidate FSHß enhancers in FSH synthesis in mice, and 3) the mechanisms through which myostatin/GDF11 regulate the human FSHß gene via its promoter and enhancer regions.