Excessive mechanotransduction in sensory neurons causes joint contractures
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.
National Institutes of Health
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, and Ardem Patapoutian. "Excessive mechanotransduction in sensory neurons causes joint contractures" Science (2023): 201-206. https://doi.org/10.1126/science.add3598