Maintaining the genetic integrity of germ cells is critical for prevention of birth defects, fertility, and the stable propagation of species. It presents a significant feat, because germ cells undergo a remarkable developmental history beginning as extraembryonic primordial germ cells (PGCs), then migrating through the embryo to the primitive gonads while simultaneously proliferating, and undergoing sex determination. Upon arrival in the primitive gonad, female PGCs directly enter meiosis, while in males, they become the mitotically renewing spermatogonial stem cell pool that continuously regenerate and initiate rounds of meiosis and spermiogenesis throughout adulthood. While genetic quality control mechanisms are vital for reproductive health, the nature of these mechanisms that are operative at different stages of germ cell development are diverse and poorly characterized. Our studies in this area seek to characterize the important genetic quality control mechanisms that operate during different stages of mammalian gametogenesis in both sexes, using genomic, proteomic and transgenic technologies in the mouse model. The projects are led by 4 highly interactive investigators, Drs. Schimenti, Weiss, Smolka, and Cohen, each specializing in the areas of reproductive biology, DNA replication and repair, meiosis, proteomics of DNA damage signaling, and mouse genetics. By utilizing state-of-the-art genome editing techniques, together with a wealth of pre-existing mouse mutants, we seek to provide a comprehensive view of key molecular mechanisms preserving the genetic integrity of our germlines, enabling us to detect, prevent, and possibly reverse risk factors that could perturb these mechanisms and predispose to reproductive health issues or transmission of birth defects to offspring.
A new study from Andrew Grimson's lab, in collaboration with Paula Cohen's lab, has identified a key pathway required for maintenance of sex chromosome telomere integrity. Using conditional knockout mice for Dicer and Dgcr8, two key enzymes required for small RNA processing, Modzelewski et al (2015) show that loss of small RNAs during prophase I leads to telomere fusion events specifically involving the X and Y chromosomes. For further information, see the May edition of Journal of Cell Science
A recent publication by Dabaja et al (2015) has identified key cell:cell interactions that are necessary to establish normal profiles of one key microRNA, miR202-5p, in Sertoli cells. This is the first example of a germ cell regulatory interaction that is necessary for miR expression in neighboring somatic cells of the testis
The lab of Center member John Schimenti recently identified the DNA damage checkpoint pathway responsible for culling oocytes that fail to repair double stranded breaks (DSBs) that occur during meiosis or which arise in a female's oocyte pool (Bolcun-Filas et al, Science 343:533-536, 2014). Using combinations of mutants involved in recombination and DNA damage responses, they found that this pathway involves signaling of checkpoint kinase 2 (CHK2) to both p53 and p63. Disruption of this checkpoint pathway restored fertility to females that normally would be deficient of all oocytes due to defects in meiotic recombination or exposure to radiation. This discovery opens the way to using available CHK2 inhibitors to protect the oocytes of women undergoing cancer therapy that would normally cause infertility.