title: Tissue-Specific Gain of RTK Signalling Uncovers Selective Cell Vulnerability during Embryogenesis.
abstract: The successive events that cells experience throughout development shape their intrinsic capacity to respond and integrate RTK inputs. Cellular responses to RTKs rely on different mechanisms of regulation that establish proper levels of RTK activation, define duration of RTK action, and exert quantitative/qualitative signalling outcomes. The extent to which cells are competent to deal with fluctuations in RTK signalling is incompletely understood. Here, we employ a genetic system to enhance RTK signalling in a tissue-specific manner. The chosen RTK is the hepatocyte growth factor (HGF) receptor Met, an appropriate model due to its pleiotropic requirement in distinct developmental events. Ubiquitously enhanced Met in Cre/loxP-based Rosa26(stopMet) knock-in context (Del-R26(Met)) reveals that most tissues are capable of buffering enhanced Met-RTK signalling thus avoiding perturbation of developmental programs. Nevertheless, this ubiquitous increase of Met does compromise selected programs such as myoblast migration. Using cell-type specific Cre drivers, we genetically showed that altered myoblast migration results from ectopic Met expression in limb mesenchyme rather than in migrating myoblasts themselves. qRT-PCR analyses show that ectopic Met in limbs causes molecular changes such as downregulation in the expression levels of Notum and Syndecan4, two known regulators of morphogen gradients. Molecular and functional studies revealed that ectopic Met expression in limb mesenchyme does not alter HGF expression patterns and levels, but impairs HGF bioavailability. Together, our findings show that myoblasts, in which Met is endogenously expressed, are capable of buffering increased RTK levels, and identify mesenchymal cells as a cell type vulnerable to ectopic Met-RTK signalling. 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.
authors.affiliation: Aix-Marseille Université, CNRS, IBDM UMR 7288, Parc Scientifique de Luminy, Case 907, Marseille, France.
authors.forename: Yannan
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Aix-Marseille Université, CNRS, IBDM UMR 7288, Parc Scientifique de Luminy, Case 907, Marseille, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Richelme
authors.affiliation: Aix-Marseille Université, CNRS, IBDM UMR 7288, Parc Scientifique de Luminy, Case 907, Marseille, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Avazeri
authors.affiliation: Aix-Marseille Université UM 105, CNRS UMR7258, Inserm U1068, CRCM, Institut Paoli-Calmettes, Marseille, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Audebert
authors.affiliation: Aix-Marseille Université, CNRS, IBDM UMR 7288, Parc Scientifique de Luminy, Case 907, Marseille, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Helmbacher
authors.affiliation: Aix-Marseille Université, CNRS, IBDM UMR 7288, Parc Scientifique de Luminy, Case 907, Marseille, France.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Dono
authors.affiliation: Aix-Marseille Université, CNRS, IBDM UMR 7288, Parc Scientifique de Luminy, Case 907, Marseille, France.
authors.forename: Flavio
authors.initials: F
authors.lastname: Maina
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics; D004622:Embryo, Mammalian; D047108:Embryonic Development / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D032446:Myoblasts / Q000378:metabolism*; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D053671:Syndecan-4 / Q000096:biosynthesis / Q000235:genetics
chemical_list: C508306:Sdc4 protein, mouse; D053671:Syndecan-4; D017228:Hepatocyte Growth Factor; C000606763:HGFR protein, mouse; D019859:Proto-Oncogene Proteins c-met