p53 pathway is involved in cell competition during mouse embryogenesis

Zhang, Guoxin; Xie, Yinyin; Zhou, Ying; Cao, Xiang; Chen, Lai; Zhang, Chenxi; Hou, Xia; Chen, Jiong; Zong, Hui; Li, Geng

doi:10.1073/pnas.1617414114

Cited by 62 publications

(43 citation statements)

References 42 publications

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“…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.…”

Section: Discussionsupporting

confidence: 91%

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

Gomes

Letzian

Saynisch

et al. 2018

Preprint

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Epithelial homeostasis requires balanced progenitor cell proliferation and differentiation, whereas disrupting this equilibrium fosters degeneration or cancer. Here we studied how cell polarity signaling orchestrates epidermal self-renewal and differentiation. Using genetic ablation, quantitative imaging, mechanochemical reconstitution and atomic force microscopy, we find that mammalian Par3 couples genome integrity and epidermal fate through shaping keratinocyte mechanics, rather than mitotic spindle orientation. Par3 inactivation impairs actomyosin contractility and viscoelasticity, and elicits mitotic failures that trigger aneuploidy, mitosisdependent DNA damage responses, p53 stabilization and premature differentiation. Importantly, reconstituting myosin activity is sufficient to restore mitotic fidelity, genome integrity, and balanced differentiation and stratification. Collectively, this study deciphers a mechanical signaling network in which Par3 acts upstream of Rho/ROCK-mediated actomyosin contractility to promote intrinsic force generation, thereby maintaining mitotic accuracy and cellular fitness at the genomic level. Disturbing this network may compromise not only epidermal homeostasis but potentially also that of other self-renewing epithelia.

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Section: Discussionsupporting

confidence: 91%

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

Gomes

Letzian

Saynisch

et al. 2018

Preprint

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“…We have shown that during the onset of differentiation, cell competition eliminates defective or mispatterned cells specifically when they are surrounded by fitter cells 12 . Similarly, cells with lower levels of c-Myc than their neighbours 12 – 14 or higher levels of p53 15 are also eliminated by cell competition in the mouse embryo. Recently in mouse, Myc -induced competition has been suggested as a mechanism to safeguard pluripotency 16 , as the low c-Myc cells eliminated by cell competition were found to be less pluripotent than their high c-Myc counterparts.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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“…Both control and Sas-4 −/− embryos show relatively high nuclear p53 around E6.5, which has been reported in WT embryos at E5.5 and E6.5 (Bowling et al, 2018). It has been suggested that p53 may be involved in cellular competition during this stage of development to eliminate less fit cells before the germline is selected (Zhang et al, 2017). Higher p53 levels in Sas-4 −/− embryos around E7 coincide with the window of the initiation of gastrulation as well as the appearance of cilia on epiblast-derived lineages (Bangs et al, 2015).…”

Section: Gradual Centriole Maturation Correlates With the Establishmementioning

confidence: 64%

Gradual centriole maturation associates with the mitotic surveillance pathway in mouse development

Xiao

Grzonka

Gerards

et al. 2020

Preprint

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Centrosomes, composed of two centrioles and pericentriolar material, organize mitotic spindles during cell division and template cilia during interphase. The first few divisions during mouse development occur without centrioles, which form around embryonic day (E) 3. However, disruption of centriole biogenesis in Sas-4 null mice leads to embryonic arrest around E9. Centriole loss in Sas-4−/− embryos causes prolonged mitosis and p53-dependent cell death. Studies in vitro discovered a similar USP28-, 53BP1-, and p53-dependent mitotic surveillance pathway that leads to cell cycle arrest. In this study, we show that an analogous pathway is conserved in vivo where 53BP1 and USP28 are upstream of p53 in Sas-4−/− embryos. The data indicates that the pathway is established around E7 of development, four days after the centrioles appear. Our data suggest that the newly formed centrioles gradually mature to participate in mitosis and cilia formation around the beginning of gastrulation, coinciding with the activation of mitotic surveillance pathway upon centriole loss.

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p53 pathway is involved in cell competition during mouse embryogenesis

Cited by 62 publications

References 42 publications

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

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

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

Gradual centriole maturation associates with the mitotic surveillance pathway in mouse development

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