We use the mouse as a paradigm for investigating the developmental biology of female gonadogenesis and early embryogenesis. In particular, we study molecular mechanisms used by oocyte-specific maternal factors to promote folliculogenesis, ensure fertilization, and sustain cleavage-stage development. My research projects include the following:
At birth, the ovary contains its full complement of germ cells, each surrounded by a single layer of granulosa cells, which together form primordial follicles. We have identified a novel, oocyte-specific, basic helix-loop-helix transcription factor, FIGLA (factor in the germline, alpha). The single-copy FIGLA gene has been disrupted in embryonic stem cells and these cells have been used to establish mouse lines. Female mice lacking FIGLA are sterile because of germ cell depletion, secondary to an inability to form primordial follicles perinatally. Investigations of downstream targets of FIGLA are providing additional insights into follicle formation and the post-natal control of germ cell identity during oogenesis.
Three zona glycoproteins (ZP1, ZP2, ZP3) are secreted during folliculogenesis to form the zona pellucida, an extracellular matrix that mediates sperm binding to the egg and induces sperm acrosome exocytosis. Historically, both binding and induction of the acrosome reaction have been attributed to a zona ligand binding to a sperm surface receptor. However, we have developed models in which sperm-egg recognition is predicated on the cleavage status of ZP2 and acrosome exocytosis is independent of sperm binding to the zona pellucida. Molecular biology and transgenesis are being used to document molecular mechanisms of sperm-egg recognition, induction of acrosome exocytosis, and post-fertilization blocks to polyspermy.
We have identified a subcortical maternal complex (SCMC) that is required for cleavage-stage embryogenesis. Members of the complex include FLOPED (factor located in oocytes permitting embryonic development), TLE6 (a Groucho-like co-repressor), MATER (maternal antigen that embryos require), and a binding partner Filia. Embryos derived from FLOPED or MATER null eggs do not progress beyond the two-cell stage and are sterile. Null embryos from other components of the complex have impaired cleavage-stage progression and decreased fecundity. Efforts are underway to define molecular mechanisms associated with activation of the embryonic genome and establishment of initial embryonic cell lineages.