Developmental Genetics of the Mammalian Ovary

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Mammalian female germ cells must successfully complete developmental programs to initial 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 novel, oocyte-specific, basic helix-loop-helix transcription factor, FIG-alpha (Factor In the Germline, alpha) and mouse lines have been established in which the single-copy Fig-alpha gene has been disrupted. Female mice lacking FIG-alpha 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. After the onset of folliculogenesis, FIG-alpha also modulates the expression of the single-copy genes that encode ZP1, ZP2 and ZP3. Normally, the three zona glycoproteins are secreted during folliculogenesis to form the zona pellucida, an extracellular matrix that mediates order-specific sperm binding to the egg (e.g., human sperm will not bind to the mouse zona pellucida). Using transgenesis, we have determined that mouse ZP1 is not required for formation of the zona pellucida, order-specific sperm binding or fertility. In contrast, both ZP2 and ZP3 are required for stable matrix formation without which mice are infertile. Although the replacement of either mouse ZP2, mouse ZP3 or both with their human homologue restores the zona pellucida matrix, it does not affect the specificity of sperm binding. Breeding studies to establish mouse lines expressing all three human zona proteins or mutant forms of the mouse zona proteins are being pursued to further investigate the molecular basis of sperm-egg interactions. 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.