Abstract
The inhibins are alpha:beta heterodimers of the TGF-beta superfamily that are essential for balancing growth and differentiation within the ovary and testis. Inhibindeficient mice (Inha−/−) develop sex cord-stromal tumors at an early age, indicating that inhibins function as tumor suppressors with gonadal specificity. Inha−/− females are infertile at 6 weeks of age, however, pharmacologic superovulation before advanced tumor growth (i.e., 3–4 weeks old) allows for fertilization, but with substantially reduced efficiency compared to wild-type controls. Combined with the observation that ovaries from adult mutants do not contain corpora lutea, these results point to defects in folliculogenesis that may be independent of tumor development. To pursue these preliminary findings, we treated 3-week-old wild-type and Inha−/− female mice with eCG (44–46 hours), or with eCG (44–46 hours) followed by hCG (6 hours), and collected ovaries to analyze follicular architecture. Stimulated wild-type ovaries contain numerous large antral follicles, each with an oocyte surrounded by two to three layers of cumulus cells that begin to expand in response to hCG. In contrast, treated mutant ovaries demonstrate an increase in the overall number of follicles, however with fewer antral follicles. The antral follicles that are present appear small and have cumulus defects. These observations suggest that inhibins are essential for the proper regulation of gonadotropin-dependent follicular development. To identify key differences in inhibin-deficient granulosa cells that may in part be responsible for the defects in folliculogenesis, we isolated total RNA from wild-type and Inha−/− granulosa cells collected from eCG- and eCG/hCGtreated mice. Gene expression profiling was performed using the Affymetrix Mouse Genome 430 2.0 microarray (n = 3 chips for each of 4 groups). Our analyses reveal that eCG-stimulated Inha−/− granulosa cells have decreased expression of cell adhesion-related genes that may correlate with the observed abnormalities in follicular organization. Moreover, these cells have increased expression of multiple cell cycle genes and decreased expression of genes involved in terminal differentiation. Together, these findings indicate that the loss of inhibins disrupts the balance of growth and differentiation within ovarian follicles, ultimately driving them toward a proliferative state. This work was supported by National Institutes of Health Grant CA60651 (to M.M.M.) and the Joseph and Matilda Melnick Endowed Fund (to A.K.N.). (poster)
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