A tension-induced mechanotransduction pathway promotes epithelial morphogenesis

Abstract

Mechanotransduction refers to the transformation of physical forces into chemical signals. It generally involves stretch-sensitive channels or conformational change of cytoskeleton-associated proteins. Mechanotransduction is crucial for the physiology of several organs and for cell migration. The extent to which mechanical inputs contribute to development, and how they do this, remains poorly defined. Here we show that a mechanotransduction pathway operates between the body-wall muscles of Caenorhabditis elegans and the epidermis. This pathway involves, in addition to a Rac GTPase, three signalling proteins found at the hemidesmosome: p21-activated kinase (PAK-1), the adaptor GIT-1 and its partner PIX-1. The phosphorylation of intermediate filaments is one output of this pathway. Tension exerted by adjacent muscles or externally exerted mechanical pressure maintains GIT-1 at hemidesmosomes and stimulates PAK-1 activity through PIX-1 and Rac. This pathway promotes the maturation of a hemidesmosome into a junction that can resist mechanical stress and contributes to coordinating the morphogenesis of epidermal and muscle tissues. Our findings suggest that the C. elegans hemidesmosome is not only an attachment structure, but also a mechanosensor that responds to tension by triggering signalling processes. We suggest that similar pathways could promote epithelial morphogenesis or wound healing in other organisms in which epithelial cells adhere to tension-generating contractile cells.

Role of the extracellular matrix in epithelial morphogenesis

“…24 When maintained to HD-like junctions, our data suggest that GIT-1 activates the homologs of the guanine nucleotide exchange factor β-PIX, of the small GTPase Rac and the p21-activated kinase PAK1, to ultimately mediate intermediate filament phosphorylation. 24 These events contribute to HD-like junction maturation, which eventually become organized perpendicular to the direction of muscle contraction and stimulate embryonic elongation. Both CeHD remodeling and elongation are defective when a component of the mechanotransduction process is lacking in the background of a weak VAB-10/Plakin mutant, or in muscle mutants (Fig.…”

“…Whether the signaling process that we uncovered 24 relays the changes in transcription when muscles cannot contract normally has not yet been tested.…”

“…24 Indeed, perlecan itself is important for CeHD remodeling 6,24 and myotactin, its presumptive receptor in the epidermis, is essential for mechanotransduction. 24 The first molecular event downstream of muscle mechanical stimuli corresponds to the maintenance of a Git1 (GRK-interacting protein 1) homolog to HD-like junctions (named GIT-1); in the absence of the muscle input it diffuses in the cytoplasm (Fig. 2B).…”

“…23 Our laboratory recently characterized a novel mechanotransduction pathway that accounts, to a large extent, for why muscledeficient embryos cannot elongate. 24 This pathway involves a tensional input provided by muscle contractions, which are transmitted through the muscle-epidermis BM to induce a mechanotransduction signaling output in the epidermis. Analysis of this pathway has brought three important lessons.…”

The optimal density of cellular solids in axial tension

“…In highly oriented tissues, such as nerve, ligament, muscle, and tendon, where tensile strength and stiffness are controlled by collagen fibers, geometrically well-defined scaffolds also provide guidance cues for cells and fibers orientation [5,13,22]. For these type of structures, the cell density and wall stiffness are key factors [4,6,23,28], which can be independently optimized to improve biological response [3,8,27]. …”