Genetic quality control in germ cell development

A major area of research in the lab concerns the mechanisms in place to maximize faithful transmission of the genome to gametes and progeny. Mammalian germ cells undergo a remarkable developmental journey. They are specified early in development and then migrate to the gonads where they ultimately undergo meiosis and differentiate to become gametes. In mice, primordial germ cells (PGCs) are first apparent as a cluster of ~45 cells in the epiblast of 6-6.5 day old embryos. They migrate to the location of the future gonads (the genital ridges) at E10.5, and proliferate rapidly to a population of ~25,000 by E13.5. After this point, only male germ cells maintain their proliferative capacity as “prospermatogonia” (a.k.a. gonocytes), but they do not resume extensive mitotic expansion until just after birth to constitute the spermatogonial stem cell pool. In females, oogonia immediately enter Prophase I of meiosis, arresting before the first meiotic division (“dictyate”). Because germ cells contain the genetic blueprint for offspring and the species, mechanisms exist to avoid transmission of mutations. A manifestation of this is the high sensitivity of cells throughout the germ lineage to genetic defects or environmental insults that affect genome integrity. The mutation rate in germ cell is far lower than in somatic cells, as a result of various quality control mechanisms.

 We have been using genetic approaches to understand the cell cycle checkpoints and DNA damage sensing mechanisms that cull out germ cells at various stages of development.  In particular, we have identified the checkpoint pathways that sense key abnormalities during meiosis that lead to cell death, namely unrepaired double stranded breaks (DSBs) and un-synapsed chromosomes.  See the publications tab for papers identifying the CHK2-p53/p63 pathway as being crucial in that regard. We have now moved to studying mechanisms of mutation suppression in PGCs, using single cell genome sequencing of cells from mice bearing DNA repair and checkpoint mutations.


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