Based on a mouse genetic system that models an enhanced wild-type form of RTKs, these results illustrate that embryonic cells are sensitive to alterations in the spatial distribution of RTK action, yet resilient to fluctuations in signalling levels of an RTK when occurring in its endogenous domain of activity.
Tissue-specific gain of RTK signalling uncovers selective cell vulnerability during embryogenesis
Yannan Fan*, Sylvie Richelme*, Emilie Avazeri*, Stéphane Audebert, Françoise Helmbacher, Rosanna Dono#, and Flavio Maina#
PLoS Genetics 11(9):e1005533 · September 2015.
* shared first authors
# shared last author
Contact: Flavio Maina – email@example.com
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.
In a wt context, limb mesenchymal cells secrete HGF required for migration of myoblasts towards the limb buds. Enhanced expression of Met in myoblasts (as assessed in Pax3-R26Met embryos) does not alter their migration due to a buffering event: the activation levels of signalling effectors such as ERKs and Akt are restrained despite enhanced Met phosphorylation. The size of each signal is representative of their phosphorylation levels. Limb mesenchymal cells are vulnerable to ectopic Met expression (as assessed in Prx1-R26Met embryos), illustrated by changes in gene expression, by failure of HGF bioavailability, and by myoblast migration defects. Alteration of HGF bioavailability can be due to: 1) upregulation of a negative interactor that would interfere with the capacity of HGF to bind/activate Met (indicated as “HGF inhibitor”), 2) downregulation of a HGF interactor acting as enhancer of its bioactivity (“HGF activator”), 3) expression of a chemorepellent factor that renders limb mesenchyme inaccessible to migrating myoblasts, or 4) HGF titration by ectopic Met in mesenchymal cells (“HGF trapping”).