206Excessive mechanotransduction in sensory neurons causes joint contractures

• 成果类型: Article
• 署名作者: Ma, Shang; Dubin, Adrienne E.; Romero, Luis O.; Loud, Meaghan; Salazar, Alexandra; Chu, Sarah; Klier, Nikola; Masri, Sameer; Zhang, Yunxiao; Wang, Yu; Chesler, Alex T.; Wilkinson, Katherine A.; Vasquez, Valeria; Marshall, Kara L.; Patapoutian, Ardem
• 署名单位: Scripps Research Institute; Howard Hughes Medical Institute; University of Tennessee System; University of Tennessee Health Science Center; University of Tennessee System; University of Tennessee Health Science Center; California State University System; San Jose State University; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS); National Institutes of Health (NIH) - USA; Baylor College of Medicine
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12760
• DOI: 10.1126/science.add3598
• 发表日期: 2023-01-13
• 页码: 201-206
• 关键词: piezo2; arthrogryposis; channel; mutations; stretch

摘要

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 D A5-like deficits. This reveals a role for somatosensory neurons: Excessive mechanosensation within these neurons disrupts musculoskeletal development.