Grant: CIHR Fellowship

Whereas development of certain simpler organisms such as the roundworm C. elegans occurs in a stereotyped fashion, with predetermined fates for each cell, mammalian development is comparatively variable: the contribution of a particular cell differs between individuals. In some organisms with variable development, competitive interactions between cells result in the elimination of certain cells. What determines which cells are eliminated, or more broadly the purpose of cell competition, are unknown. The timing of endogenous cell competition in the mouse embryo may provide clues; this point, approximately five days into embryonic development, follows a burst of rapid cell division that stresses the machinery that normally ensures genomic fidelity during DNA replication. Therefore, the timing of competition overlaps with a period of enhanced DNA damage accumulation secondary to replicative stress. Although the majority of mutations probably have no consequence, the accumulation of mutations and/or specific mutations could compromise the long-term function of a cell and its progeny. We hypothesize that cell competition during development serves to eliminate cells with damaged DNA. To test this hypothesis, first, we will study whether and how DNA-damage influences cell competition using a cell culture system where the dose and variety of DNA-damaging agent can be precisely controlled. Second, we will study the relationship between endogenous DNA-damage and cell competition during early mouse embryogenesis, during the time window of extreme replicative stress and pervasive cell competition. Third, we will ask if equivalent cell competition extends to other cell lineages, particularly the germline, where DNA damage would have transgenerational consequences. This work should reveal fundamental developmental mechanisms likely to underlie tumor avoidance, regenerative capacity and longevity that could potentially be harnessed in regenerative medicine and cancer therapy.