Follicle-stimulating hormone regulates expression and activity of epidermal growth factor receptor in the murine ovarian follicle.
Fertility depends on the precise coordination of multiple events within the ovarian follicle to ensure ovulation of a fertilizable egg. FSH promotes late follicular development, including expression of luteinizing hormone (LH) receptor by the granulosa cells. Expression of its receptor permits the subsequent LH surge to trigger the release of ligands that activate EGF receptors (EGFR) on the granulosa, thereby initiating the ovulatory events. Here we identify a previously unknown role for FSH in this signaling cascade. We show that follicles of Fshb(-/-) mice, which cannot produce FSH, have a severely impaired ability to support two essential EGFR-regulated events: expansion of the cumulus granulosa cell layer that encloses the oocyte and meiotic maturation of the oocyte. These defects are not caused by an inability of Fshb(-/-) oocytes to produce essential oocyte-secreted factors or of Fshb(-/-) cumulus cells to respond. In contrast, although expression of both Egfr and EGFR increases during late folliculogenesis in Fshb(+/-) females, these increases fail to occur in Fshb(-/-) females. Remarkably, supplying a single dose of exogenous FSH activity to Fshb(-/-) females is sufficient to increase Egfr and EGFR expression and to restore EGFR-dependent cumulus expansion and oocyte maturation. These studies show that FSH induces an increase in EGFR expression during late folliculogenesis and provide evidence that the FSH-dependent increase is necessary for EGFR physiological function. Our results demonstrate an unanticipated role for FSH in establishing the signaling axis that coordinates ovulatory events and may contribute to the diagnosis and treatment of some types of human infertility.
Departments of Obstetrics and Gynecology, Biology, and Research Institute-McGill University Health Centre; Montreal, QC, Canada H3A 1A1; and.
Stephany
S
El-Hayek
Departments of Obstetrics and Gynecology, Research Institute-McGill University Health Centre; Montreal, QC, Canada H3A 1A1; and Research Laboratory on Human Reproduction Fertility Clinic, Université Libre de Bruxelles Erasme, 1070 Brussels, Belgium.
Isabelle
I
Demeestere
Departments of Obstetrics and Gynecology, Biology, and Research Institute-McGill University Health Centre; Montreal, QC, Canada H3A 1A1; and Medicine, McGill University, Montreal, QC, Canada H3A 1A1; hugh.clarke@mcgill.ca.
Hugh J
HJ
Clarke
D000818:Animals; D066246:ErbB Receptors / Q000235:genetics / Q000502:physiology*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D006080:Ovarian Follicle / Q000502:physiology*
D005640:Follicle Stimulating Hormone; D066246:ErbB Receptors
EGFR; FSH; follicle; granulosa; ovary