BOEX, Myriam; COTTIN, Steve; HALLIEZ, Marius; BAUCHE, Stephanie; BUON, Celine; SANS, Nathalie; MONTCOUQUIOL, Mireille; MOLGO, Jordi; AMAR, Muriel; FERRY, Arnaud; LEMAITRE, Megane; ROUCHE, Andree; LANGUI, Dominique; BASKARAN, Asha; FONTAINE, Bertrand; MESSEANT, Julien; STROCHLIC, Laure

doi:10.1126/scisignal.abg4982

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BOEX, Myriam
Centre de recherche en Myologie – U974 SU-INSERM

COTTIN, Steve
Centre de recherche en Myologie – U974 SU-INSERM

HALLIEZ, Marius
Centre de recherche en Myologie – U974 SU-INSERM

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Science Signaling. 2022-05-17, vol. 15, n° 734

Résumé en anglais

The development of the neuromuscular junction (NMJ) requires dynamic trans-synaptic coordination orchestrated by secreted factors, including Wnt family morphogens. To investigate how these synaptic cues in NMJ development are transduced, particularly in the regulation of acetylcholine receptor (AChR) accumulation in the postsynaptic membrane, we explored the function of Van Gogh-like protein 2 (Vangl2), a core component of Wnt planar cell polarity signaling. We found that conditional, muscle-specific ablation of Vangl2 in mice reproduced the NMJ differentiation defects seen in mice with global Vangl2 deletion. These alterations persisted into adulthood and led to NMJ disassembly, impaired neurotransmission, and deficits in motor function. Vangl2 and the muscle-specific receptor tyrosine kinase MuSK were functionally associated in Wnt signaling in the muscle. Vangl2 bound to and promoted the signaling activity of MuSK in response to Wnt11. The loss of Vangl2 impaired RhoA activation in cultured mouse myotubes and caused dispersed, rather than clustered, organization of AChRs at the postsynaptic or muscle cell side of NMJs in vivo. Our results identify Vangl2 as a key player of the core complex of molecules shaping neuromuscular synapses and thus shed light on the molecular mechanisms underlying NMJ assembly. Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.< Réduire

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Animals

Cell Polarity

Fatty Acids

Monounsaturated

Mice

Muscle Fibers

Skeletal / metabolism

Nerve Tissue Proteins / metabolism

Protein-Tyrosine Kinases

Receptors

Cholinergic / genetics Receptors

Cholinergic / metabolism

Synapses / genetics

Synapses / metabolism

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The cell polarity protein Vangl2 in the muscle shapes the neuromuscular synapse by binding to and regulating the tyrosine kinase MuSK

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