Predicting gene networks in human oocyte meiosis.

Meiosis is the characteristic feature of sexual reproduction; its molecular regulation has been preserved throughout eukaryotic evolution. The defining stage of meiosis is prophase I (Fig. 1), in which homologous chromosomes pair and remain tethered until the first meiotic division, when they must segregate equally into daughter cells that then enter meiosis II. The importance of this stage is underscored by the fact that approximately 50% of all spontaneous miscarriages are due to nondisjunction errors at the first meiotic division [1, 2]. Although a large body of literature exists to confirm the molecular conservation of these processes across eukaryotes, one of the more startling observations from mammalian meiosis is that there are differences between the sexes in their meiotic progression [3] and, more specifically, in the source of meiotic errors in humans, because approximately 90% of chromosomally aneuploid human fetuses arise as a result of errors in maternal meiosis I [2, 5]. The timing and progression of meiosis also vary between the sexes. In females, oogonia enter meiosis during fetal development, arresting toward the end of prophase I in a prolonged state of diplotene known as dictyate arrest (Fig. 1). Meiosis resumes after puberty, when cohorts of oocytes are stimulated to undergo the first meiotic division with each estrous cycle and only complete the second meiotic division upon fertilization. Thus, oogenesis begins during fetal life, but it may take months (in rodents) or years (in primates) to complete. By contrast, male meiosis is not interrupted by arrest periods, and it occurs in a continuum from around the time of (or just prior to) puberty, after which spermatogonia continue to enter prophase I in waves throughout the life of the individual. What becomes obvious from these temporal differences is the inherent difficulty in studying meiotic events in females. The availability of female meiotic material is hampered, not only by the fact that one must retrieve such tissue from fetuses, but also because of the extremely limited amount of ovarian tissue available at these stages. Even in the mouse, where animal numbers may not be limiting, the use of female meiotic tissues for high-throughput biochemical, proteomics, or genomics research is hindered because of the small size of the fetal ovary. These issues are exacerbated in humans, with the result that very few studies have focused on meiotic events in human fetal ovaries [6–12]. Most of the published reports focus on confirmation in human oocytes of the molecular pathways involved in synapsis and recombination derived from mouse data [6, 13]. Several groups have attempted to address whether and how events during fetal meiosis in human oocytes may be a causative factor in human nondisjunction [6, 8, 10, 14]. These studies have mainly used surface spread chromosome preparations (e.g., Fig. 2), and although substantial data have been accumulated, little new information has been obtained concerning the details of genetic regulation that is unique/ specific to humans. An exciting report from Zheng et al. [15] in this issue of Biology of Reproduction attempts to overcome these difficulties by providing the first functional gene network for human fetal germ cells, HFOnet. This network provides a tool to predict and assess the meiotic role of genes from multiple pathways in a tissue (the human fetal ovary) that is poorly accessible through traditional laboratory sources.