Xenotransplantation: a new paradigm for human meiosis

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DESCRIPTION (provided by applicant): Fertility in women is a product of multiple molecular pathways that start during embryogenesis and involve the entry of germ cells into meiosis, together with the structural reorganization of the ovary that results in primordial follicle formation. These events are poorly understood in women because of the difficulty in obtaining fetal ovarian samples of later gestational ages. The importance of understanding these events is underscored by the observation that meiosis is highly error-prone in women, with 70% of pregnancy losses being due to maternal meiosis I errors. While some limited analysis has been performed on human fetal oocytes during early meiotic prophase I, it has been hard to examine later stages of prophase I and the entry into dictyate arrest which occurs at around the time of birth and which triggers the important structural changes within the developing ovary. To overcome these difficulties, this R21 application seeks to establish a novel xenotransplantation system for analyzing human meiosis and ovarian development. In aim 1, we will establish the xenografting methodology using human fetal ovaries and different immunocompromised mouse hosts, to optimize the conditions for xenograft establishment. Xenografts will be assessed for cell viability and development by an array of immunohistochemical and cytogenetic criteria. In aim 2, we will examine the progression of xenotransplanted human oocytes through prophase I, taking advantage of our significant expertise in mammalian meiosis to analyze homologous chromosome interactions, recombination dynamics and crossover formation. In aim 3, we will examine the onset of dictyate arrest in human oocytes to define the molecular/cellular events during stromal reorganization and primordial follicle formation. This model provides a new paradigm for studying ovarian development, a poorly understood process, but defects in which may contribute to the high aneuploidy rates observed in women compared to other mammals, premature ovarian failure and other fertility issues affecting women.