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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 proteins1. Mechanotransduction is crucial for the physiology of several organs and for cell migration2,3. 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.

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Figure 1: Muscle tension promotes C. elegans hemidesmosome maturation.
Figure 2: PAK-1 function is required for CeHD maturation.
Figure 3: PAK-1-induced intermediate-filament phosphorylation depends on muscle tension.
Figure 4: GIT-1 maintenance at CeHDs in a tension-dependent manner and PIX-1 promote PAK-1 activation.

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Acknowledgements

We are grateful to H.-J. Cheng, the CGC and NBP-Japan, L. Lim, J. Nance, C. Gally and L. Broday for reagents, as well as M. Argentini for technical advice. We thank J. Ahringer for a discussion, and O. Pourquié, J.-L. Bessereau, S. Jarriault and members of the Labouesse laboratory (C. Gally, I. Kolotueva, N. Osmani and S. Quintin) for critical reading of the manuscript. This work was supported by grants from the ANR, ARC and EU (STREP-FP6 programme) (M.L.) and by institutional funds from the CNRS and INSERM.

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Contributions

H. Zhang and M.L. designed the study, analysed the data and wrote the paper. H. Zhang conducted most of the experiments. F.L. and H. Zahreddine made some initial observations (tension-change modification of the epidermis, and PAK-1 distribution and mutant phenotype) that proved to be essential for designing the study. D.R. provided technical help. M.K. helped to design and analyse the pressing experiment.

Corresponding author

Correspondence to Michel Labouesse.

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Zhang, H., Landmann, F., Zahreddine, H. et al. A tension-induced mechanotransduction pathway promotes epithelial morphogenesis. Nature 471, 99–103 (2011). https://doi.org/10.1038/nature09765

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