Expression of Extracellular Matrix Components Is Disrupted in the Immature and Adult Estrogen Receptor β-Null Mouse Ovary

Within the ovary, Estrogen Receptor beta (ER beta) is localized to the granulosa cells of growing follicles. 17 beta-estradiol (E2) acting via ER beta augments the actions of follicle stimulating hormone in granulosa cells, leading to granulosa cell differentiation and formation of a preovulatory follicle. Adult ER beta-null females are subfertile and possess ovaries with reduced numbers of growing follicles and corpora lutea. Because the majority of E2 production by granulosa cells occurs once puberty is reached, a role for ER beta in the ovary prior to puberty has not been well examined. We now provide evidence that lack of ER beta disrupts gene expression as early as post-natal day (PND) 13, and in particular, we identify a number of genes of the extracellular matrix (ECM) that are significantly higher in ER beta-null follicles than in wildtype (WT) follicles. Considerable changes occur to the ECM occur during normal folliculogenesis to allow for the dramatic growth, cellular differentiation, and reorganization of the follicle from the primary to preovulatory stage. Using quantitative PCR and immunofluorescence, we now show that several ECM genes are aberrantly overexpressed in ER beta-null follicles. We find that Collagen11a1, a protein highly expressed in cartilage is significantly higher in ER beta-null follicles than WT follicles as early as PND 13, and this heightened expression continues through PND 23-29 into adulthood. Similarly, Nidogen 2, a highly conserved basement membrane glycoprotein, is elevated in ER beta-null follicles at PND 13 into adulthood, and is elevated specifically in the ER beta-null focimatrix, a basal lamina-like matrix located between granulosa cells. Focimatrix laminin and Collagen IV expression were also higher in ER beta-null ovaries than in WT ovaries at various ages. Our findings suggest two novel observations: a) that ER beta regulates granulosa cell gene expression ovary prior to puberty, and b) that ER beta regulates expression of ECM components in the mouse ovary.