Objective The importance of mechanical forces in biology is well accepted, yet an integrated view of their mode of action in vivo is lacking. We intend to characterize in-depth the physical forces and cellular processes that coordinate the morphogenesis of different cell types contributing to an organ, taking the C. elegans embryo as a paradigm.We will achieve this by pursuing three axes:1. Building on our discovery of a hemidesmosome-based mechanotransduction pathway that operates between contracting muscles and epidermal cells, we will combine genetic analysis with single-molecule biophysical methods to address three issues. i) What is the primary mechanosensor responding to tension within hemidesmosomes and how does it work? ii) How are all epidermal targets of muscle tension activated? iii) What is the biophysical mechanism stabilizing epidermal cells between muscle contractions?2. We will test several features of a finite element model predicting a key role of microtubule-based epidermal stiffness and hydrostatic pressure in elongation. We will combine quantitative mechanical measures with force biosensors and laser ablation to define how these resistive forces contribute to embryo elongation along the anterior-posterior axis.3. To extend our conclusions to the medical field, we will knockdown homologues of proteins identified in C. elegans, as well as proteins of the same families, in keratinocytes with partially damaged hemidesmosomes. Cells will be submitted to wound assays or grown on a stretchable substrate. Positive hits will be further characterized and tested in mouse models with partially defective hemidesmosomes.We foresee that this project will identify conserved proteins and processes relaying mechanical forces, and thus shed light on the mechanical basis of morphogenesis. We also expect our work to have strong impact in medicine, since the outcome of many pathologies, including wound healing and cancer, is thought to be strongly influenced by forces. Fields of science engineering and technologyelectrical engineering, electronic engineering, information engineeringelectronic engineeringsensorsbiosensorsnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesphysical sciencesclassical mechanicsfluid mechanicsfluid staticsmedical and health sciencesclinical medicineembryologynatural sciencesphysical sciencesopticslaser physics Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) ERC-AG-LS3 - ERC Advanced Grant - Cellular and Developmental Biology Call for proposal ERC-2011-ADG_20110310 See other projects for this call Funding Scheme ERC-AG - ERC Advanced Grant Host institution CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS EU contribution € 1 237 637,08 Address RUE MICHEL ANGE 3 75794 Paris France See on map Region Ile-de-France Ile-de-France Paris Activity type Research Organisations Administrative Contact Julie Zittel (Ms.) Principal investigator Michel Labouesse (Prof.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data Beneficiaries (2) Sort alphabetically Sort by EU Contribution Expand all Collapse all CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS France EU contribution € 1 237 637,08 Address RUE MICHEL ANGE 3 75794 Paris See on map Region Ile-de-France Ile-de-France Paris Activity type Research Organisations Administrative Contact Julie Zittel (Ms.) Principal investigator Michel Labouesse (Prof.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data CENTRE EUROPEEN DE RECHERCHE EN BIOLOGIE ET MEDECINE Participation ended France EU contribution € 1 257 866,92 Address Rue Laurent Fries 1 67404 Illkirch Graffenstaden See on map Region Grand Est Alsace Bas-Rhin Activity type Research Organisations Administrative Contact Steve Brooks (Dr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data
