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Title: Investigating the role of nutrient-sensing pathways and senescence in stem cell competition and early mammalian development
Author: Bowling, Sarah
ISNI:       0000 0004 9350 1495
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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Cell competition is a quality control mechanism that eliminates cells which are viable but less fit than surrounding cells. The outcome of cell competition is enhanced organismal fitness as the process prevents the propagation of cells which are oncogenic, mispatterned, or otherwise sub-optimal. Cell competition research has largely been performed in flies, although recently it was found that cells in the early mammalian embryo are sensitive to competitive interactions. However, the underlying mechanisms driving the elimination of less fit cells in this system remain largely unknown. Here, we interrogate competition mechanisms in the early mammalian embryo. First, we postulate that senescence may have a role in mediating the out-competition of defective cells. While our evidence does not provide support for this framework, we observed an upregulation of senescence-associated phenotypes in the early post-implantation epiblast. Second, we find that the confrontation of cells with different fitness levels leads to a repression of mTOR signalling in the less-fit cell type. This repression is sufficient to trigger apoptosis, and hyperactivation of the mTOR pathway rescues loser cell elimination and allows less-fit tetraploid cells to contribute to later developmental stages. Finally, we find that less-fit cell types are marked by elevated levels of p53, and loss of p53 prevents both loser cell elimination and mTOR pathway repression. Furthermore, mutations affecting p53/mTOR activity increase the competitive ability of cells within the embryo and cause tissue overgrowths that prevent proper morphogenesis and patterning. Our results shed light on the mechanisms of cell competition in development but also allude to a role for cell competition in the elimination of damaged or nutrient-stressed cells prior to gastrulation.
Supervisor: Rodriguez, Tristan ; Gil, Jesus Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral