Abstract
Oocytes develop within ovarian follicles that nurture and regulate oocyte maturation. The LH surge induces a cascade of gene expression leading to formation of the hyaluronan (HA) rich cumulus matrix around the oocyte. This cumulus oocyte complex (COC) is composed of high concentrations of HA cross-linked by several HA-binding proteins. Null mutation of several COC matrix genes results in ovulation defects demonstrating the importance of the composition and structure of the COC; but the mechanisms by which the matrix promotes ovulation are unknown. We hypothesised that HA, via activation of its receptor CD44 on cumulus cells, regulates cytoskeletal function, cell adhesion and migration, and that acquired cumulus cell motility facilitates ovulation. We investigated cellular signaling and cellular phenotypes occurring in response to the formation of the HA-rich COC matrix. Expression of CD44 was upregulated 5 to 6-fold in cumulus cells following 6 or 12h hCG (LH analog) stimulation. Signal transducers of CD44 action; Tiam1, a guanine exchange factor, and Rac1, an actin cytoskeleton remodelling Rho-family GTPase, were present in cumulus cells but not regulated by hCG. Induction of migratory and invasive capacity of cumulus cells by hCG was demonstrated using transwell migration and ECM invasion assays. Cumulus cell migration increased 8-fold 10h after hCG compared with cumulus cells from untreated mice. These cumulus cells also showed the capacity to invade through a matrigel barrier. Inhibitors of the CD44-assembled cell migration complex demonstrated the importance of this pathway in the migratory and invasive phenotype of cumulus cells. These results demonstrate that CD44 is a key factor in the assembly of a macromolecular complex facillitating cell motility in cumulus cells at the time of ovulation, and suggest that cumulus cells in the expanded COC undergo epithelial-mesenchymal transition to become invasive motile cells which may play a key role mediating ovulation.
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