Multiple signaling defects in the absence of RIP140 impair both cumulus expansion and follicle rupture.

The nuclear receptor corepressor RIP140 is essential in the ovary for ovulation, but is not required for follicle growth and luteinization. To identify genes that may be subject to regulation by RIP140 or play a role in ovulation, we compared ovarian gene expression profiles in untreated immature wild-type and RIP140 null mice and after treatment with pregnant mare serum gonadotropin and human chorionic gonadotropin. Many genes involved in signaling, extracellular matrix formation, cell-cell attachment, and adhesion were aberrantly regulated in the absence of RIP140, varying according to the hormone status of the mice. Notable among these was the reduced expression of a number of genes that encode components of signaling pathways and matrix proteins required for cumulus expansion, a key remodeling process necessary for ovulation. Histological analysis confirmed that cumulus expansion in RIP140 null mice is reduced, oocyte detachment from the mural cell wall is impaired, and follicles fail to rupture in response to LH. Although the expression of many genes involved in cumulus cell expansion was reduced, there was a subset of genes involved in extracellular matrix formation and cell-cell interactions that was up-regulated and may interfere with ovarian tissue remodeling. We propose that widespread gene dysregulation in ovarian tissues in the absence of RIP140 leads to the anovulatory phenotype. This helps to define an important role for RIP140 in the regulation of multiple processes leading to ovulation.