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Title: The role of mitochondria in the cell-to-cell interactions that regulate fitness during early mouse embryonic development
Author: de Lima, Ana Raquel Abrunhosa Carvalho
ISNI:       0000 0004 9356 7945
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2019
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The early stages of embryonic development involve a rewiring of transcriptional, epigenetic, signalling and metabolic pathways that define cell identity. The substantial nature of the changes taking place creates a large potential for the emergence of defective cells, that need to be eliminated to prevent them from contributing to the future foetus. One quality control that ensures this elimination is cell competition, a fitness sensing mechanism that eliminates cells that, although viable, are less fit than their neighbours. Here we investigated the nature of competitive interactions to understand what are the key features of unfit cells that are recognised as a read-out of cell fitness. First, we studied mouse embryonic stem cells (mESCs) with defective BMP signalling (Bmpr1a-/-), that are eliminated by their wild-type neighbours, and found these have metabolic defects, including loss of mitochondrial membrane potential and decreased mitochondrial respiration. Second, we tested if the direct manipulation of mitochondrial biology can trigger cell competition. We found that mESCs with deletion of mitofusin 2 (Mfn2-/-) or dynamin-related protein 1 (Drp1-/-), which are genes important for mitochondrial morphology and dynamics, are eliminated by wild-type cells. This led us to test if more subtle changes in the mitochondria of mESCs could impact on their relative fitness. By analysing mESCs on the same nuclear background, but with different mitochondrial DNA (mtDNA), we demonstrate that even changes in mtDNA sequences can trigger cell selection by cell competition. Finally, using single cell RNA sequencing and analysis of mitochondrial activity, we identify that mitochondrial defects are key signature of the cells eliminated from the early mouse embryo. Together, our results suggest that cell competition acts during early development to select cells with the fittest mitochondria to give rise to the embryo, preventing the propagation of deleterious defects to the adult organism and future generations.
Supervisor: Rodríguez, Tristan ; Carling, David Sponsor: British Heart Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral