Developmental Genetics of the Mammalian Ovary

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Mammalian female germ cells must successfully complete developmental programs to initiate folliculogenesis that lead to mature gametes capable of fertilization and the transfer of genetic material to the next generation. At birth the ovary contains its full complement of germ cells, each surrounded by a single layer of granulosa cells which together form the primordial follicles. We have identified a basic helix-loop-helix transcription factor, FIG-alpha (Factor In the Germline, alpha) and female mice lacking this regulatory factor are sterile because of germ cell depletion secondary to an inability to form primordial follicles. Identification of downstream targets of FIG-alpha should provide additional insights into the molecular basis of follicle formation and other developmental programs important for successful oogenesis. After the onset of folliculogenesis, FIG-alpha also modulates the expression of the single-copy genes that encode ZP1, ZP2 and ZP3. Together they form the zona pellucida surrounding ovulated mouse eggs and two (ZP2 and ZP3), are reported 'sperm receptors'. After fertilization, the zona pellucida is modified ad minimum by cleavage of ZP2 and sperm no longer bind. Cross-taxa sperm binding is limited among mammals and human sperm do not bind to mouse eggs. Using transgenesis to replace mouse ZP2 and/or ZP3 with human homologues, mouse lines with human-mouse chimeric zonae pellucidae have been established. Unexpectedly, human sperm do not bind to huZP2 and huZP2/huZP3 rescue eggs, but mouse sperm bind, in vitro fertilized eggs progress to two-cell embryos, and rescue mice are fertile. Also unanticipated, human ZP2 remains uncleaved after fertilization and mouse sperm continue to bind early rescue embryos. These observations are consistent with a model in which the supramolecular structure of the zona pellucida necessary for sperm binding is modulated by the cleavage status of ZP2. Late in oogenesis, the oocyte becomes transcriptionally inactive and much of the maternal RNA is degraded during meiotic maturation and ovulation. At fertilization, both gametes are transcriptionally inert and the major activation of the embryonic genome occurs at the two-cell stage. The sperm brings little but its genome to fertilization and the activation of early development programs must depend on maternal factors. MATER (Maternal Antigen That Embryos Require) is a cytoplasmic protein that is present in growing oocytes and persists in early embryos. Mice lacking MATER have normal folliculogenesis and ovulate eggs. Although fertilization takes place, embryos do not progress beyond the early cleavage stage. Males are unaffected and MATER represents a maternal effect gene product critical for mammalian development. Investigations are underway to determine its role in transition of the terminally differentiated germ cell into the totipotent stem cells of the early embryo.