Wnt proteins contribute to neuromuscular junction formation through distinct signaling pathways

Development. 2017 May 1;144(9):1712-1724. doi: 10.1242/dev.146167. Epub 2017 Mar 27.


Understanding the developmental steps that shape formation of the neuromuscular junction (NMJ) connecting motoneurons to skeletal muscle fibers is crucial. Wnt morphogens are key players in the formation of this specialized peripheral synapse, but their individual and collaborative functions and downstream pathways remain poorly understood at the NMJ. Here, we demonstrate through Wnt4 and Wnt11 gain-of-function studies in cell culture or in mice that Wnts enhance acetylcholine receptor (AChR) clustering and motor axon outgrowth. By contrast, loss of Wnt11 or Wnt-dependent signaling in vivo decreases AChR clustering and motor nerve terminal branching. Both Wnt4 and Wnt11 stimulate AChR mRNA levels and AChR clustering downstream of activation of the β-catenin pathway. Strikingly, Wnt4 and Wnt11 co-immunoprecipitate with Vangl2, a core component of the planar cell polarity (PCP) pathway, which accumulates at embryonic NMJs. Moreover, mice bearing a Vangl2 loss-of-function mutation (loop-tail) exhibit fewer AChR clusters and overgrowth of motor axons bypassing AChR clusters. Together, our results provide genetic and biochemical evidence that Wnt4 and Wnt11 cooperatively contribute to mammalian NMJ formation through activation of both the canonical and Vangl2-dependent core PCP pathways.

Keywords: Mouse; Neuromuscular junction; Planar cell polarity; Vangl2; Wnt; β-catenin signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism
  • Cell Polarity
  • Embryo, Mammalian / metabolism
  • Extracellular Space / metabolism
  • Mice, Inbred C57BL
  • Mutation / genetics
  • Nerve Tissue Proteins / metabolism
  • Neuromuscular Junction / metabolism*
  • Phenotype
  • Receptors, Cholinergic / metabolism
  • Signal Transduction*
  • Synapses / metabolism
  • Wnt Proteins / metabolism*
  • Wnt4 Protein / metabolism*


  • Ltap protein, mouse
  • Nerve Tissue Proteins
  • Receptors, Cholinergic
  • Wnt Proteins
  • Wnt11 protein, mouse
  • Wnt4 Protein