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.
Show 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.
Matching journals
The top 4 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- Transient receptor potential canonical 5 (TRPC5) mediates inflammatory mechanical pain 93%
- Variants in ALDH1A2 reveal an anti-inflammatory role for retinoic acid and a new class of disease-modifying drugs in osteoarthritis 92%
- Loss of TDP-43 function and rimmed vacuoles persist after T cell depletion in a xenograft model of sporadic inclusion body myositis 92%
Similar papers in this journal
Similar papers in this journal
- Cerebellar nuclei cells produce distinct pathogenic spike signatures in mouse models of ataxia, dystonia, and tremor 93%
- Touch receptor end-organ innervation and function requires sensory expression of the transcription factor Meis2 93%
- A library of lineage-specific driver lines connects developing neuronal circuits to behavior in the Drosophila Ventral Nerve Cord. 92%
Similar papers in this journal
- Combinatorial chloride and calcium channelopathy in myotonic dystrophy 93%
- ACVR1 antibodies exacerbate heterotopic ossification in fibrodysplasia ossificans progressiva (FOP) by activating FOP-mutant ACVR1 92%
- Deciphering the molecular landscape of human peripheral nerves: implications for diabetic peripheral neuropathy 92%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.