EDITOR’S CHOICE IN NEUROSCIENCE
A skeletal muscle isn’t a lot use with out a sign telling it to maneuver. In vertebrates, this signaling occurs on the neuromus-cular junction (NMJ), a synaptic connection between motor neurons and muscle fibers. As soon as stimulated, a neuron will launch the neurotransmitter acetylcholine, which then traverses the synapse to bind specialised receptors on the floor of the muscle, triggering a contraction.
A collection of molecular equipment is required for the event and upkeep of the NMJ, which might in any other case turn out to be disorganized over time. One well-known participant is muscle-specific kinase (MuSK), which types a posh concerned in cell signaling. Latest analysis has additionally implicated the Wnt household of proteins, peptides concerned in a number of developmental pathways in animals. Now, Laure Strochlic and colleagues on the Institute of Myology in Paris say they’ve recognized one other essential protein element, offering a greater mechanistic understanding of how these junctions are shaped.
Strochlic’s group beforehand reported that Vangl2, a transmembrane protein discovered on each the neuron and muscle sides of the NMJ, interacts with sure Wnt
proteins—and that mice with mutated Vangl2 have NMJ defects. For his or her newest venture, Strochlic, PhD scholar Myriam Boëx, and colleagues created location-
particular mouse knockouts, disrupting Vangl2 perform both within the motor neuron or in skeletal muscle. Knocking out the protein within the neuron had little impact on NMJ structure, the crew discovered. However disrupting Vangl2 within the muscle resulted in mice with structurally disorganized junctions, diminished synaptic transmission, and weak spot of their diaphragm or leg muscle mass.
In vitro biochemical and genetics assays prompt that Vangl2 straight binds to MuSK and mediates Wnt-induced MuSK signaling, Strochlic provides. Though the exact particulars of the interactions aren’t but clear, the findings level to Vangl2 being an vital element of the advanced that helps develop and keep the NMJ, she says.
Geneticist Robert Burgess, who research mouse fashions of neuromuscular illness at The Jackson Laboratory in Maine and was not concerned within the work, says he discovered the crew’s experiments “very clear and convincing.” Particularly, the group’s physiological experiments “present this isn’t simply an esoteric factor that’s altering the form of the neuromuscular junction a little bit bit—it truly is impacting perform.” Though Vangl2 mutations diminished muscle power to a lesser diploma than do mutations in different essential NMJ proteins, “I consider . . . it’s an actual impact,” on the premise of the information offered, he provides.
Strochlic’s crew is now digging deeper into Wnt signaling in NMJ improvement, and is working with a clinician to discover the research’s scientific implications for situations that trigger muscle weak spot, similar to myasthenia. “We’re at present wanting within the databases of myasthenic sufferers all around the world [to see] if a few of the molecules, together with Vangl2, are mutated,” she says.
M. Boëx et al., “The cell polarity protein Vangl2 within the muscle shapes the neuromuscular synapse by binding to and regulating the tyrosine kinase MuSK,” Sci Sign, 15:eabg4982, 2022.