| The Notch signaling pathway is evolutionarily conserved and regulates cell lineage decisions. In Drosophila, the Notch pathway is required for oogenesis, therefore it was determined whether this pathway was required for proper ovarian follicle development in mammals. The spatiotemporal expression of Notch family genes in the mouse ovary was determined. Notch2, Notch3, and Jagged2 were expressed in granulosa cells in an overlapping pattern. There was a characteristic loss of expression of Notch2 and Jagged2 in those cells adjacent to the developing antrum. Jagged1 was expressed exclusively in oocytes in preantral follicles. The downstream target genes of Notch, Hairy-enhancer of split-1 and -5, and the Hairy-enhancer of split-related genes HESR1, HESR2, and HESR3, were expressed in developing follicles in patterns reflective of receptor and ligand binding. In cultured preantral follicles, inhibiting Notch activation using a gamma-secretase inhibitor caused the upregulation of hyaluronan synthase-2 and cyclooxygenase-2, markers of cumulus granulosa cells. Also, activation of Notch in cumulus-oocyte complexes by soluble Jagged1 inhibited cumulus expansion. These data indicate that Jagged1-mediated activation of Notch inhibits cumulus differentiation. Lunatic fringe regulates the binding of Notch to its ligands, and Lunatic fringe-null mice were reported to be infertile. Lunatic fringe-deficient ovaries were smaller than those of wild-type, and were found to contain approximately half the endowed primordial follicles compared to wild-type, at postnatal day 4. Adult Lunatic fringe-deficient ovaries demonstrated aberrant follicle development. Using in vitro fertilization, very few eggs from Lunatic fringe-null mice developed to the two-cell stage and no embryos developed past the eight-cell stage. These data support a model in which Notch signaling is required for normal folliculogenesis. |
