J Cell Sci. 2021 Feb 1;jcs.252957. doi: 10.1242/jcs.252957. Online ahead of print.
Georgios Efthymiou 1, Agata Radwanska 1, Anca-Ioana Grapa 1 2, Stéphanie Beghelli-de la Forest Divonne 1 3, Dominique Grall 1, Sébastien Schaub 1, Maurice Hattab 1, Sabrina Pisano 4, Mallorie Poet 4, Didier F Pisani 5, Laurent Counillon 5, Xavier Descombes 2, Laure Blanc-Féraud 2, Ellen Van Obberghen-Schilling 6
Affiliations
1 Université Côte d’Azur, CNRS, INSERM, iBV, Nice, France.
2 Université Côte d’Azur, Inria, CNRS, i3S, Nice, France.
3 Centre Antoine Lacassagne, Nice, France.
4 Université Côte d’Azur, Inserm, CNRS, IRCAN, Nice, France.
5 Université Côte d’Azur, CNRS, LP2M, Nice, France.
6 Université Côte d’Azur, CNRS, INSERM, iBV, Nice, France vanobber@unice.fr.
Abstract
Cellular fibronectin (FN) variants harboring one or two alternatively spliced Extra Domains (B and A) play a central bioregulatory role during development, repair processes and fibrosis. Yet, how the Extra Domains impact fibrillar assembly and function of the molecule remains unclear. Leveraging a unique biological toolset and image analysis pipeline for direct comparison of the variants, we demonstrate that the presence of one or both Extra Domains impacts FN assembly, function and physical properties of the matrix. When presented to FN-null fibroblasts, Extra Domain-containing variants differentially regulate pH homeostasis, survival, and TGF-β signaling by tuning the magnitude of cellular responses, rather than triggering independent molecular switches. Numerical analyses of fiber topologies highlight significant differences in variant-specific structural features and provide a first step for the development of a generative model of FN networks to unravel assembly mechanisms and investigate the physical and functional versatility of extracellular matrix landscapes.
PMID: 33526715
DOI: 10.1242/jcs.252957