Excessive Mechanotransduction in Sensory Neurons Causes Joint Contractures in a Mouse Model of Arthrogryposis

Ma, S.; Dubin, A. E.; Romero, L. O.; Loud, M.; Salazar, A.; Wang, Y.; Chesler, A.; Wilkinson, K. A.; Vasquez, V.; Marshall, K. L.; Patapoutian, A.

doi:10.1101/2022.06.07.495164

bioRxiv · 10.1101/2022.06.07.495164

Excessive Mechanotransduction in Sensory Neurons Causes Joint Contractures in a Mouse Model of Arthrogryposis

Ma, S.·Dubin, A. E.·Romero, L. O.·Loud, M.·Salazar, A.·Wang, Y.·Chesler, A.·Wilkinson, K. A.·Vasquez, V.·Marshall, K. L.·Patapoutian, A.

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Abstract

Distal arthrogryposis (DA) is a collection of rare disorders characterized by congenital joint contractures. Most DA mutations are in muscle- and joint-related genes, and the anatomical defects originate cell-autonomously within the musculoskeletal system. However, gain-of-function (GOF) mutations in PIEZO2, a principal mechanosensor in somatosensation, cause DA subtype 5 via unknown mechanisms. We show that expression of a GOF PIEZO2 mutation in proprioceptive sensory neurons mainly innervating muscle spindles and tendons is sufficient to induce DA5-like phenotypes in mice. Overactive PIEZO2 causes anatomical defects via increased activity within the peripheral nervous system during postnatal development. Remarkably, Botox and a dietary fatty acid that modulates PIEZO2 activity markedly reduce DA5-like deficits. This reveals an unexpected role for somatosensory neurons: excessive mechanosensation within these neurons disrupts musculoskeletal development.

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Ma, S., Dubin, A. E., Romero, L. O., Loud, M., Salazar, A., Wang, Y., Chesler, A., Wilkinson, K. A., Vasquez, V., Marshall, K. L., Patapoutian, A.. 2022-06-08. Excessive Mechanotransduction in Sensory Neurons Causes Joint Contractures in a Mouse Model of Arthrogryposis. https://doi.org/10.1101/2022.06.07.495164

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