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Excessive mechanotransduction in sensory neurons causes joint contractures.

Shang MaAdrienne E DubinLuis O RomeroMeaghan LoudAlexandra SalazarSarah ChuNikola KlierSameer MasriYunxiao ZhangYu WangAlexander T CheslerKatherine A WilkinsonValeria VásquezKara L MarshallArdem Patapoutian
Published in: Science (New York, N.Y.) (2023)
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.
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