Research Summary: Regulation of Ovarian Follicle Growth during the Mammalian Reproductive Cycle
The primary goal of the laboratory is to understand the biological, cellular, and molecular mechanisms that regulate the reproductive axis and the ovarian follicle. The study of normal reproductive function requires measurement of fluctuating hormone levels (endocrine), identification of local ovarian factors that control follicle development, and an understanding of the signaling mechanisms that cue cellular action. Infertility arises when critical regulatory pathways are interrupted. Fertility may also be impacted by therapeutics such as those used to control the spread of cancer.
Endocrine Control of Reproduction
In the 1930’s D.R. McCullagh reported the presence of a non-steroidal substance in testis able to regulate normal pituitary function in rats. Decades later, proteins able to inhibit FSH secretion from the pituitary, while having little effect on levels of luteinizing hormone (LH), were identified. The proteins were called inhibins, and two isoforms of the gonadally derived protein have been studied primarily for the role each plays in regulation of follicle stimulating hormone (FSH) secretion from the anterior pituitary. In the absence of inhibin, for example in ovariectomized animals or postmenopausal women, serum FSH levels rise precipitously. The two inhibin isoforms, inhibin A and inhibin B, have been well characterized in both male and female across a number of species. Inhibin B is the primary isoform detected in adult male serum, while both isoforms are secreted and regulated during the menstrual cycle, at times during pregnancy, and are absent following menopause.
Inhibin acts as an antagonist to a related hormone called activin, a protein that regulates a wide range of physiological activities throughout the body. Inhibin and activin are prototypical members of the transforming growth factor beta (TGFβ) superfamily of ligands and receptors. A highly conserved cysteine pattern is common to all TGFβ ligands, resulting in a “cysteine knot” fold. Activins are homodimers of the inhibin beta subunits (activin A, βA/βA, activin B, βB/βB, and activin AB, βA/βB). Sequence divergence distances the inhibin α-subunit from the main subgroups of the family tree, which are the activin/TGFβ subfamily, bone morphogenetic protein (BMP) subfamily, and decapentaplegic-Vg-related (DVR) subfamily. Activn binds to a cell surface receptor (ActRIIA or ActRIIB).
Figure 1: The interaction site of the activin beta subunit (red) and the type II receptor ActRIIB extracellular domain (blue). Amino acids on ligand (yellow) and receptor (green) reflect the hydrophobic nature of the interaction. Activin binding to ActRIIB at the cell plasma membrane allows for recruitment of the type I receptor ALK4, and subsequent intracellular signaling through phosphorylation of Smad proteins.
Activin may also be regulated by a bioneutralizing binding protein follistatin.
Figure 2: Two follistatin 288 molecules (blue and green) engulfing an activin A homodimer (red). Follistatin covers the type I and type II receptor binding sites on activin, providing a high affinity interaction, and potent method for abrogation of activin activity.