1. Transcriptional regulation of follicle-stimulating hormone synthesis
Follicle-stimulating hormone (FSH) is a glycoprotein produced by gonadotrope cells of the anterior pituitary gland. FSH stimulates ovarian follicle growth in females and spermatogenesis in males. Gonadotropin-releasing hormone (GnRH) from the hypothalamus and intra-pituitary activins are generally regarded as the two principal drivers of FSH synthesis in vivo. For almost two decades, we have been investigating the mechanisms of activin action. FSH is a dimeric protein composed of α and β subunits. Activins stimulate transcription of the FSHβ subunit (Fshb) gene. Using in vitro and in vivo approaches, we discovered necessary roles for the signaling proteins SMAD3 and SMAD4, and the transcription factor FOXL2, in Fshb expression. Our ongoing investigations are defining how these proteins regulate Fshb transcription. We are also characterizing the receptors through which activins and related TGFβ superfamily ligands regulate FSH synthesis in vivo.
2. Mechanisms of GnRH action
GnRH is the principal brain neuropeptide through which the brain controls reproductive physiology. It acts on the GnRH receptor (GnRHR), a G protein-coupled receptor expressed on gonadotrope cells, to stimulate the synthesis of FSH and luteinizing hormone (LH). FSH and LH, collectively referred to as the gonadotropins, stimulate sex steroid hormone production by the gonads. Clinically, GnRHR antagonists are used to treat hormone-dependent diseases such as prostate cancer and endometriosis. Paradoxically, GnRHR agonists can be used for the same purpose, as continuous exposure to GnRH inhibits GnRHR activity. Under normal physiological conditions, GnRH is released from the brain episodically and the GnRHR must ‘see’ these pulses to drive synthesis and secretion of gonadotropins. Moreover, pulse frequency varies and differentially regulates the gonadotropins. At low GnRH pulse frequency, gonadotropes preferentially secrete FSH. At high frequencies, LH secretion exceeds FSH. Using in vivo and in vitro approaches, we are investigating the mechanisms through which gonadotropes decode GnRH pulse frequency. Moreover, how GnRH stimulates FSH production is poorly described. We produced a novel mouse model in which the animals harbor a modification to the GnRHR that selectively impairs FSH synthesis and secretion. We are using these mice and complementary cell line models to determine how GnRH regulates FSH.
3. FSH actions in bone
Though FSH is best-known for its actions in the gonads, research over the last decade suggests that the hormone might have effects in other tissues, including in bone and fat. Using both in vitro and in vivo approaches, we are investigating if FSH has actions in bone-resorbing osteoclasts and, if so, whether its effects are mediated via the classical FSH receptor.
4. Molecular mechanisms of IGSF1-deficiency syndrome
In 2012, we and our collaborators discovered that mutations in the immunoglobulin superfamily, member 1 (IGSF1) gene cause an X-linked form of congenital central hypothyroidism. IGSF1 is a transmembrane glycoprotein of unknown function expressed in thyrotrope cells of the anterior pituitary gland. Thyrotropes synthesize and secrete thyroid-stimulating hormone (TSH) in response to thyrotropin-releasing hormone (TRH) from the hypothalamus. In the absence of IGSF1, the pituitary expresses the TRH receptor at reduced levels. As a result, TRH stimulation of TSH is impaired, leading to reduced drive on thyroid hormone production. We are investigating how IGSF1 functions under normal conditions and how the loss of these functions culminates in reduced TRH receptor expression.