Fig. 3.

Molecular cues in NMJ formation/stabilization: a cross-talk between pre- and post-synaptic components. The agrin–muscle-specific kinase (MuSK)-rapsyn-AchR pathway is schematized. LRP4 acts as a co-factor for MuSK in agrin signaling. Agrin activates MuSK to cluster AChRs through the cytoplasmic linker protein rapsyn. Neuregulin that binds to ErbB receptors may also induce AChR transcription and agrin would direct AChR clustering. Neuregulin signaling also occurs from the axon to control Schwann cell survival. Schwann cells also belong to the tripartite NMJ with MN and muscle, and are essential for axon maintenance. Homophilic adhesion molecules such as NCAM are expressed on the surface of the three cell types composing the NMJ. Receptors to neurotrophic factors such as TrkB, p75 and GDNF receptors, are expressed at the MN surface. Actin regulators are present in the post-synaptic compartment, in particular Nogo-A, dystrophin and β-catenin. β-Catenin interacts with rapsyn and α-catenin to favor AChR clustering. β-Catenin-dependent transcription is also necessary for NMJ maintenance. Myogenin is involved in AchR expression, stabilization and clustering. Synaptic muscle fiber basal lamina is rich in laminin β2. It binds to and clusters the P/Q-type calcium channels that flank active zones and recruit other pre-synaptic components