Excessive Mechanotransduction in Sensory Neurons Causes Joint Contractures

Authors

Shang Ma
Adrienne E Dubin
Luis O Romero
Meaghan Loud
Alexandra Salazar
Sarah Chu
Nikola Klier
Sameer Masri
Yunxiao Zhang
Yu Wang
Alex T Chesler
Katherine A Wilkinson
Valeria Vásquez
Kara L Marshall
Ardem Patapoutian

Publication Date

1-13-2023

Journal

Science

Abstract

Distal arthrogryposis (DA) is a collection of rare disorders that are 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 mutations in PIEZO2, a principal mechanosensor in somatosensation, cause DA subtype 5 (DA5) through unknown mechanisms. We show that expression of a gain-of-function PIEZO2 mutation in proprioceptive sensory neurons that mainly innervate muscle spindles and tendons is sufficient to induce DA5-like phenotypes in mice. Overactive PIEZO2 causes anatomical defects through increased activity within the peripheral nervous system during postnatal development. Furthermore, botulinum toxin (Botox) and a dietary fatty acid that modulates PIEZO2 activity reduce DA5-like deficits. This reveals a role for somatosensory neurons: Excessive mechanosensation within these neurons disrupts musculoskeletal development.

Keywords

Animals, Mice, Arthrogryposis, Contracture, Mechanotransduction, Cellular, Mutation, Sensory Receptor Cells, Ion Channels