New frontiers in cell competition†

Beco, Simon de; Ziosi, Marcello; Johnston, Laura

doi:10.1002/dvdy.23783

Cited by 65 publications

(57 citation statements)

References 81 publications

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“…In ESCs, the exit from self-renewal into differentiation triggers cell competition and associated apoptosis (de Beco et al, 2012;Levayer and Moreno, 2013;Wagstaff et al, 2013). Hence, selective apoptosis is perhaps triggered as a result of PrE differentiation, and this is suppressed by limiting concentrations of LIF.…”

Section: Discussionmentioning

confidence: 99%

LIF supports primitive endoderm expansion during pre-implantation development

Morgani

Brickman

2015

Development

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Embryonic stem cells (ESCs) are pluripotent cell lines that can be maintained indefinitely in an early developmental state. ESC culture conditions almost always require the cytokine LIF to maintain selfrenewal. As ESCs are not homogeneous but contain multiple populations reminiscent of the blastocyst, identifying the target cells of LIF is necessary to understand the propagation of pluripotency. We recently found that LIF acts under self-renewing conditions to stimulate the fraction of ESCs that express extraembryonic markers, but has little impact on pluripotent gene expression. Here, we report that LIF has two distinct roles: it blocks early epiblast (Epi) differentiation, and it supports the expansion of primitive endoderm (PrE)-primed ESCs and PrE in vivo. We find that activation of JAK/ STAT signalling downstream of LIF occurs initially throughout the preimplantation embryo, but later marks the PrE. Moreover, the addition of LIF to cultured embryos increases the GATA6 + PrE population, whereas inhibition of JAK/STAT signalling reduces both NANOG + epiblast and GATA6 + PrE. The reduction of the NANOG + Epi might be explained by its precocious differentiation to later Epi derivatives, whereas the increase in PrE is mediated both by an increase in proliferation and inhibition of PrE apoptosis that is normally triggered in embryos with an excess of GATA6 + cells. Thus, it appears that the relative size of the PrE is determined by the number of LIF-producing cells in the embryo. This suggests a mechanism by which the embryo adjusts the relative ratio of the primary lineages in response to experimental manipulation.

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Section: Discussionmentioning

confidence: 99%

LIF supports primitive endoderm expansion during pre-implantation development

Morgani

Brickman

2015

Development

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“…In contrast to the classical cell autonomous responses of growth arrest or apoptosis, a noncell autonomous mechanism called cell competition, first uncovered in Drosophila, determines whether a cell is to survive or be eliminated based on its relative "fitness" in comparison with its neighboring cells (12,13). Therefore, otherwise viable but less-fit cells may be eliminated in a competitive environment to ensure the overall fitness of the tissue and, in turn, the organism.…”

Section: Mdm4mentioning

confidence: 99%

p53 pathway is involved in cell competition during mouse embryogenesis

Zhang

Xie

Zhou

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The function of tumor suppressor p53 has been under intense investigation. Acute stresses such as DNA damage are able to trigger a high level of p53 activity, leading to cell cycle arrest or apoptosis. In contrast, the cellular response of mild p53 activity induced by low-level stress in vivo remains largely unexplored. Murine double minute (MDM)2 and MDM4 are two major negative regulators of p53. Here, we used the strategy of haploinsufficiency of Mdm2 and Mdm4 to induce mild p53 activation in vivo and found that Mdm2+/−Mdm4+/− double-heterozygous mice exhibited normal embryogenesis. However, closer examination demonstrated that the Mdm2+/−Mdm4+/− cells exhibited a growth disadvantage and were outcompeted during development in genetic mosaic embryos that contained wild-type cells. Further study indicated the out-competition phenotype was dependent on the levels of p53. These observations revealed that cells with mild p53 activation were less fit and exhibited altered fates in a heterotypic environment, resembling the cell competition phenomenon first uncovered in Drosophila. By marking unfit cells for elimination, p53 may exert its physiological role to ensure organ and animal fitness.

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“…In flies, the Hippo pathway has been implicated as a driver of cell competition upstream of myc (Neto-Silva et al 2010;de Beco et al 2012). The pathway con-sists of a kinase cascade (consisting of the Hippo and Warts kinases), which negatively regulates a transcriptional coactivator (Yorkie).…”

Section: Regulation By Localized Cell Interactionsmentioning

confidence: 99%

Organ-Size Regulation in Mammals

Penzo–Méndez

Stanger

2015

Cold Spring Harb Perspect Biol

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The control of organism and organ size is a central question in biology. Despite the attention it has received, our understanding of how adult organ size is determined and maintained is still incomplete. Early work has shown that both autonomous and regulated mechanisms drive vertebrate organ growth, and both intrinsic and extrinsic cues contribute to organ size. The molecular nature of organ-size determinants has been the subject of intense study, and major pathways, which underlie cell interactions controlling cell compartment size,

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New frontiers in cell competition†

Cited by 65 publications

References 81 publications

LIF supports primitive endoderm expansion during pre-implantation development

LIF supports primitive endoderm expansion during pre-implantation development

p53 pathway is involved in cell competition during mouse embryogenesis

Organ-Size Regulation in Mammals

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