Tissue-Specific Gain of RTK Signalling Uncovers Selective Cell Vulnerability during Embryogenesis

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The need to achieve precise control of RTK activation is highlighted by human pathologies such as congenital malformations and cancers caused by aberrant RTK signalling. Identifying strategies to restrain RTK activity in cancer and/or to reactivate RTKs for counteracting degenerative processes is the focus of intense research efforts. We designed a genetic system to enhance RTK signalling during mouse embryogenesis in order to examine the competence of cells to deal with changes in RTK inputs. Our data reveal that most embryonic cells are capable of: 1) handling moderate perturbations in Met-RTK expression levels, 2) imposing a threshold of intracellular signalling activation despite elevated Met-RTK inputs, and/or 3) integrating variable quantitative levels of Met-RTK signalling within biological responses. Our results also establish that certain cell types, such as limb mesenchyme, are particularly vulnerable to alterations of the spatial distribution of RTK expression. The vulnerability of limb mesenchyme to enhanced Met levels is illustrated by gene expression changes, by interference with HGF chemoattractant effects, and by loss of accessibility to incoming myoblasts, leading to limb muscle defects. These findings highlight how resilience versus vulnerability to RTK fluctuation is strictly linked to cell competence and to the robustness of the developmental programs they undergo.

Vyšlo v časopise: Tissue-Specific Gain of RTK Signalling Uncovers Selective Cell Vulnerability during Embryogenesis. PLoS Genet 11(9): e32767. doi:10.1371/journal.pgen.1005533
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005533

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