P53 and mTOR signalling determine fitness selection through cell competition during early mouse embryonic development

Abstract

Ensuring the fitness of the pluripotent cells that will contribute to future development is important both for the integrity of the germline and for proper embryogenesis. Consequently, it is becoming increasingly apparent that pluripotent cells can compare their fitness levels and signal the elimination of those cells that are less fit than their neighbours. In mammals the nature of the pathways that communicate fitness remain largely unknown. Here we identify that in the early mouse embryo and upon exit from naive pluripotency, the confrontation of cells with different fitness levels leads to an inhibition of mTOR signalling in the less fit cell type, causing its elimination. We show that during this process, p53 acts upstream of mTOR and is required to repress its activity. Finally, we demonstrate that during normal development around 35% of cells are eliminated by this pathway, highlighting the importance of this mechanism for embryonic development.

Polarity signaling ensures epidermal homeostasis by coupling cellular mechanics and genomic integrity

“…Our data further strongly suggest that genome instability and the resulting DNA damage responses act as defining factors for differentiated epidermal cell fate. These data are in agreement with recent developmental studies linking p53 to embryonic stem cell differentiation 33 and data from mouse embryos exposing p53 as driver of differentiated fate by reducing cell competition and fitness 34,35 . Our findings extend these developmental data to a more general concept that orchestrates tissue homeostasis.…”

Charting the emergent organotypic landscape of the mammalian gut endoderm at single-cell resolution

“…1a-b), we isolated cells from sequentially-staged wild-type mouse embryos between E3.5 and E8. 75, including associated endoderm-containing extraembryonic tissues. Cohorts of cells representing each population sampled were processed for scRNA-seq library preparation using the 10x Genomics Chromium platform ( Fig.…”

“…3). It is unclear whether this EPI-to-VE differentiation reflects a removal of 'less-fit' cells from the pluripotent epiblast compartment [72][73][74][75] or an active recruitment of cells to the VE. In the context of cell competition-based model for the EPI, cell engulfment has been proposed as the mechanism of cell removal.…”

“…a, Force directed layout of trajectory of endoderm cells from blastocyst to midgestation, corresponding to E3.5-E8. 75 Orange, black and green arrowheads point to high expression in ParE, VE and EPI, respectively. f, Dynamics of TF ratios as lineages are specified: Gata6/Nanog and Gata6/Fgf4 along EPI; Nanog/Gata6 and Fgf4/Gata6 along PrE, compared to changes in differential potential (dotted line).…”

Epiblast formation by Tead-Yap-dependent expression of pluripotency factors and competitive elimination of unspecified cells

“…Cell competition is required to eliminate such unnecessary cells produced by developmental fluctuations to establish a naïve epiblast. For the second qualitycontrol step, as described previously, cell competition is required to eliminate the prematurely differentiation-primed cells (Diaz-Diaz et al, 2017) and defective cells produced by the increased proliferation rate or karyotypically abnormal cells to prevent these cells from contributing to the germline (Bowling et al, 2018). Thus, two quality-control steps via cell competition may function as safeguards against developmental fluctuations and errors to ensure the production and expansion of a high-quality epiblast to support correct embryonic and germ line development.…”