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WIREs Dev Biol
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Cell competition in vertebrate organ size regulation

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The study of animal organ size determination has provided evidence of the existence of organ‐intrinsic mechanisms that ‘sense’ and adjust organ growth. Cell competition, a form of cell interaction that equalizes cell population growth, has been proposed to play a role in organ size regulation. Cell competition involves a cell‐context dependent response triggered by perceived differences in cell growth and/or proliferation rates, resulting in apoptosis in growth‐disadvantaged cells and compensatory expansion of the more ‘fit’ cells. The mechanisms that allow cells to compare growth are not yet understood, but a number of genes and pathways have been implicated in cell competition. These include Myc, the members of the Hippo, JAK/STAT and WNT signaling pathways, and the Dlg/Lgl/Scrib and the Crb/Std/PatJ membrane protein complexes. Cell competition was initially characterized in the Drosophila imaginal disc, but several recent studies have shown that cell competition occurs in mouse embryonic stem cells and in the embryonic epiblast, where it plays a role in the regulation of early embryo size. In addition, competition‐like behavior has been described in the adult mouse liver and the hematopoietic stem cell compartment. These data indicate that cell competition plays a more universal role in organ size regulation. In addition, as some authors have suggested that similar types of competitive behavior may operate in during tumorigenesis, there may be additional practical reasons for understanding this fundamental process of intercellular communication. WIREs Dev Biol 2014, 3:419–427. doi: 10.1002/wdev.148 This article is categorized under: Early Embryonic Development > Development to the Basic Body Plan Plant Development > Cell Growth and Differentiation Comparative Development and Evolution > Organ System Comparisons Between Species
Cell competition in the mouse embryo. (a) Schematic representation of the mouse mosaic embryos generated by injection of embryonic stem (ES) cells carrying the inducible randomo mosaic (iMOS) transgene in wild‐type or Myc mutant blastocysts. Allele recombination results in expression of either a CFP (IMOSWt) or a Myc‐YFP (IMOST1‐Myc) cassette. The Myc genetic dosages resulting from different recombinant allele and recipient genotype combinations are indicated. (b) Transgenic E9.5 embryos. Contribution of YFP cells is increased in embryos as the Myc dosage difference increases, while embryo size remains unchanged. (Reprinted with permission from Ref . © 2014, Nature Publishing Group.)
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Potential role of cell competition in tumor formation. Cell transformation involves successive mutagenic events promoting unrestrained cell growth. In the presence of active cell competition mechanisms, these events would likely also result in increased cellular fitness. Early precancerous cells would then behave as super‐competitors and expand by eliminating the surrounding healthy cells, perceived as less fit. Cell competition would thus result in formation of precancerous fields, increasing the likelihood of cells accumulating additional mutations leading to tumor formation.
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Competition is driven through diffusing factors in Drosophila S2 cells. (a) Cell competition occurs in wild‐type and dMyc overexpressing cells separated by a permeable membrane. (b) Medium conditioned by dMyc overexpressing super‐competitor cells does not induce apoptosis in wild‐type cells. (c) Successive condition by super‐competitors and wild‐type cells triggers apoptosis of naïve wild‐type cells, indicating that cells must ‘sense’ each other before releasing a ‘killing signal’ into the medium.
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Schematic representation of the signaling pathways associated with cell competition. Results from studies in both Drosophila and mouse are summarized, mouse gene symbols are shown. Dashed lines represent proposed interactions.
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Comparative Development and Evolution > Organ System Comparisons Between Species
Plant Development > Cell Growth and Differentiation
Early Embryonic Development > Development to the Basic Body Plan