We use the mouse as a paradigm for investigating the developmental biology of female gonadogenesis and early embryogenesis. In particular, we investigate molecular mechanisms of oocyte-specific maternal factors that promote folliculogenesis, ensure fertilization and support early development. Our research projects include:
Folliculogenesis: 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). When the single-copy Figla gene is ablated, female mice are sterile because of germ cell depletion secondary to an inability to form primordial follicles. Identification of downstream targets of FIGLA should provide additional insights into the molecular basis of follicle formation and provide candidate genes for maternal effects that disrupt embryogenesis.
Fertilization: Monospermic fertilization is essential for the onset of development. One sperm is required, but two are lethal. A major arbiter of this constricted window of opportunity is the zona pellucida that surrounds ovulated eggs and pre-implantation embryos. The extracellular human and mouse zonae pellucidae are composed of four (huZP1-4) or three (moZP1-3) glycoproteins, respectively. We have developed models in which sperm-egg recognition is predicated on the N-terminus of ZP2 which is cleaved by ovastacin, a metalloendoprotease released from egg cortical granules following fertilization. Molecular biology and mouse transgenesis are being used to validate these models and investigate subsequent events of mammalian fertilization.
Early Development: We have identified maternal factors, including 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, Tle6 or Mater null eggs, do not progress beyond the 2-cell stage, do not activate the embryonic genome and are uniformly infertile. Efforts are underway to define the molecular basis of these and other maternal effect phenotypes, particularly those that affect activation of the embryonic genome.