The Jackson Laboratory
Bar Harbor, ME
Investigates the genetic regulation of meiosis and the mechanisms of male fertility to understand how errors in meiosis can lead to developmental abnormalities.
Several genes discovered by the Reproductive Genomics Program affect chromosome behavior and progress of meiosis, providing both new alleles of previously known genes, as well as mutations in previously unknown genes. Among the latter, we found that the Spata22 gene is essential for one or more key events of early meiotic prophase, including normal synapsis and repair of meiotic DNA double-strand breaks. The mutant phenotype of Eif4g3 revealed for the first time the role of specific translational regulation in the progress of mammalian meiosis and spermatogenesis.
A long-standing goal of our laboratory has been to understand how the germ cell regulates the onset of the meiotic division after recombination is complete. Previous work in our laboratory demonstrated the importance of cell-cycle-active kinases, and more recent work has provided cellular and biochemical evidence for a role of the polo-like kinases in promoting desynapsis of paired homologous chromosomes. Identification of the substrates of PLK1 provides new ways to investigate mechanisms of desynapsis. Additionally, genetic evidence reveals unexpected complexity in the regulation of the onset of the meiotic division phase; from the Reproductive Genomics Program we discovered that mutation in the Eif4g3 gene, encoding eukaryotic translation initiation factor 4, gamma 3 arrests meiotic prophase at the decision point for desynapsis and entry into the division phase. Global protein translation is not affected, but, strikingly, HSPA2, a chaperone protein for CDK1 kinase, is absent in the mutant spermatocytes. in spite of the presence of Hspa2 transcript, identifying a specific substrate for translational regulation by EIF4G3. These results provide the first evidence for acute and selective translational control of meiotic exit in mammalian spermatocytes.Together, our studies are providing information about both the temporal order and regulatory relationships of the earliest events in the transition from meiotic prophase to metaphase.
In collaboration with the Paigen and Carter laboratories, we investigate genetic and cellular aspects of the initiation of meiotic recombination, focusing on the role of the protein PRDM9. As show by Paigen and colleagues, PRDM9 is the major activator of mammalian recombination hotspots. We integrate analysis of these studies with our ongoing work on the importance of meiosis-specific proteins involved in the structural maintenance of meiotic chromosomes.