Developmental Genetics of the Mammalian Ovary

哺乳动物雌性生殖细胞必须成功地完成发育程序，才能启动卵泡发生，从而产生能够受精的成熟配子，并将遗传物质转移到下一代。在出生时，卵巢包含完整的生殖细胞，每个生殖细胞被一层颗粒细胞包围，这些颗粒细胞共同形成原始卵泡。我们已经确定了一种基本的螺旋-环-螺旋转录因子FIG-α(生殖系中的因子，α)，缺乏这种调节因子的雌性小鼠是不育的，因为继发于无法形成原始卵泡的生殖细胞枯竭。FIG-α下游靶点的识别将为卵泡形成的分子基础和其他对成功的卵子发生至关重要的发育程序提供更多的见解。在卵泡发生开始后，FIG-α还调节编码ZP1、ZP2和ZP3的单拷贝基因的表达。它们共同形成了小鼠排卵卵子周围的透明带，其中两个(ZP2和ZP3)被报道为“精子受体”。受精后，透明带被ZP2裂解，精子不再结合。哺乳动物之间的精子跨类群结合有限，而人类精子不与小鼠卵子结合。利用转基因技术，用人的同源物取代小鼠ZP2和/或ZP3，建立了人-鼠嵌合透明带小鼠品系。出乎意料的是，人类精子不与huZP2和huZP2/huZP3救助卵结合，但小鼠精子结合，体外受精卵进展为两细胞胚胎，救助鼠是有生育能力的。同样出乎意料的是，人类ZP2在受精后仍未被切割，小鼠的精子继续与早期救援胚胎结合。这些观察结果与一个模型一致，在该模型中，精子结合所需的透明带超分子结构受到ZP2切割状态的调节。在卵子发生的后期，卵母细胞在转录上变得不活跃，在减数分裂成熟和排卵期间，母体的大部分RNA被降解。在受精时，两个配子在转录上都是惰性的，胚胎基因组的主要激活发生在两细胞阶段。精子除了它的基因组外，对受精几乎没有什么影响，早期发育计划的激活必须取决于母体因素。Mater(胚胎所需的母体抗原)是一种细胞质蛋白，存在于发育中的卵母细胞中，并在早期胚胎中持续存在。缺乏物质的小鼠有正常的卵泡发生和排卵。虽然受精发生了，但胚胎不会超过早期卵裂阶段。雄性不受影响，MATER代表着一种对哺乳动物发育至关重要的母性效应基因产物。目前正在进行研究，以确定它在将终末分化的生殖细胞转变为早期胚胎的全能干细胞中所起的作用。

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.