GENOMICS OF MALE GERM CELL SURVIVAL AND MAINTENANCE MECHANISMS

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Project II: Genomics of Male Germ Cell Survival and Maintenance Mechanisms Mary Ann Handel, Project Leader Meiosis is particularly vulnerable to interruption and arrest at prophase I stages, which is when two key events are occurring: chromosome recombination/synapsis and passage of germ cells from the basal to the adluminal compartment of the seminiferous epithelium, an environment that fosters completion of meiosis. Although both meiotic recombination events autonomous to the germ cell and seminiferous epithelium events mediated by the Sertoli cells are required for progress beyond this early stage of meiotic prophase, most of the mechanisms remain poorly understood. Mutations generated by the ReproGenomics Program provide opportunities to investigate the testicular regulation of critical events of early meiotic prophase. The spcar1-4, sjsermatocyte arrest 1-4, mutations cause arrest at this early and vulnerable stage of prophase. In Aim 1, the causes and consequences for the germ cell of meiotic arrest will be determined using techniques of molecular cytology and gene expression analysis. Because there is no a priori knowledge whether these mutations act in the germ cell or in the soma to cause spermatocyte arrest, this will be resolved in Aim 2 by spermatogonial stem cell (SSC) transplantation assays. In Aim 3, the downstream effects of the mutations on Sertoli cells will be investigated, using meiotic arrest mutations as a tool to examine aspects of cell-cell interactions and gene expression critical for Sertoli cell maturation and testis differentiation. The genomic regions defined for these mutations do not include any genes known to be involved in meiotic pathways, ensuring that this work will, in the analyses of Aim 4, identify new or unsuspected genes and mechanisms, either intrinsic or extrinsic to the germ cell, essential for meiotic progress. Together the four aims will tackle different aspects of the meiotic arrest phenotypes of different mutations affecting the same stage of meiosis. Relevance to Public Health: By discovery of novel mechanisms controlling early meiotic prophase, this work will provide insight into common human male infertility syndromes and the origins of aneuploidy.