Neurons and muscle tissue
Neurons and muscle tissue

A Novel Player at the Neuromuscular Junction

The muscle transmembrane protein Vangl2 helps organize the development and maintenance of connections between muscles and motor neurons, a study concludes.

Catherine Offord
Catherine Offord

Catherine is a senior editor at The Scientist.

View full profile.


Learn about our editorial policies.

Sep 12, 2022

ABOVE: © ISTOCK.COM, koto_feja

EDITOR’S CHOICE IN NEUROSCIENCE

A skeletal muscle isn’t much use without a signal telling it to move. In vertebrates, this signaling happens at the neuromus-cular junction (NMJ), a synaptic connection between motor neurons and muscle fibers. Once stimulated, a neuron will release the neurotransmitter acetylcholine, which then traverses the synapse to bind specialized receptors on the surface of the muscle, triggering a contraction.

A suite of molecular machinery is required for the development and maintenance of the NMJ, which can otherwise become disorganized over time. One well-known player is muscle-specific kinase (MuSK), which forms a complex involved in cell signaling. Recent research has also implicated the Wnt family of proteins, peptides involved in multiple developmental pathways in animals. Now, Laure Strochlic and colleagues at the Institute of Myology in Paris say they have identified another crucial protein component, providing a better mechanistic understanding of how these junctions are formed.

Strochlic’s group previously reported that Vangl2, a transmembrane protein found on both the neuron and muscle sides of the NMJ, interacts with certain Wnt
proteins—and that mice with mutated Vangl2 have NMJ defects. For their latest project, Strochlic, PhD student Myriam Boëx, and colleagues created location-
specific mouse knockouts, disrupting Vangl2 function either in the motor neuron or in skeletal muscle. Knocking out the protein in the neuron had little effect on NMJ architecture, the team found. But disrupting Vangl2 in the muscle resulted in mice with structurally disorganized junctions, reduced synaptic transmission, and weakness in their diaphragm or leg muscles.

In the normal development and maintenance of the neuromuscular junction (left), structural organization is maintained thanks to signaling by proteins such as musclespecific kinase (MuSK), Vangl2, and Wnt ligands, researchers propose. In mice whose muscles don’t produce Vangl2 (right), junctions are instead disorganized. Compared with control animals, mice lacking muscle Vangl2 have more-dispersed postsynaptic acetylcholine receptors, muscles that are withdrawn, and a reduction in synaptic transmission. As a result, the muscles aren’t properly innervated and mice experience muscle weakness.
In the normal development and maintenance of the neuromuscular junction (left), structural organization is maintained thanks to signaling by proteins such as muscle-specific kinase (MuSK), Vangl2, and Wnt ligands, researchers propose. In mice whose muscles don’t produce Vangl2 (right), junctions are instead disorganized. Compared with control animals, mice lacking muscle Vangl2 have more-dispersed postsynaptic acetylcholine receptors, muscles that are withdrawn, and a reduction in synaptic transmission. As a result, the muscles aren’t properly innervated and mice experience muscle weakness. WEB | PDF


In vitro biochemical and genetics assays suggested that Vangl2 directly binds to MuSK and mediates Wnt-induced MuSK signaling, Strochlic adds. Although the precise details of the interactions aren’t yet clear, the findings point to Vangl2 being an important component of the complex that helps develop and maintain the NMJ, she says.

Geneticist Robert Burgess, who studies mouse models of neuromuscular disease at The Jackson Laboratory in Maine and was not involved in the work, says he found the team’s experiments “very clear and convincing.” In particular, the group’s physiological experiments “show this isn’t just an esoteric thing that’s changing the shape of the neuromuscular junction a little bit—it really is impacting function.” Although Vangl2 mutations reduced muscle strength to a lesser degree than do mutations in other crucial NMJ proteins, “I believe . . . it’s a real effect,” on the basis of the data provided, he adds. 

Strochlic’s team is now digging deeper into Wnt signaling in NMJ development, and is working with a clinician to explore the study’s clinical implications for conditions that cause muscle weakness, such as myasthenia. “We are currently looking in the databases of myasthenic patients all over the world [to see] if some of the molecules, including Vangl2, are mutated,” she says.

M. Boëx et al., “The cell polarity protein Vangl2 in the muscle shapes the neuromuscular synapse by binding to and regulating the tyrosine kinase MuSK,” Sci Signal, 15:eabg4982, 2022.

Membership Open House!

Enjoy OPEN access to Premium Content for a limited time
Outline of a human head with an abstract wave. Plexus effect.

Interested in exclusive access to more premium content?

Already a member?