Figure 8.

Summary scheme of LRP4:MuSK signaling. (A) Signaling events differentially induce AChR clustering toward either NMJ formation and motor neuron innervation or toward formation of aneural clusters. (B) Details of neural and aneural NMJ signaling via LRP4:MuSK activation. In canonical (agrin-dependent) NMJ signaling, binding of agrin to co-receptor LRP4 stimulates activation of MuSK and downstream effector functions (left). In this pathway, Neurotrypsin likely operates as a regulator through specific agrin cleavage at α and β sites; non-canonical (i.e., agrin-independent) events such as cross-talk with Wnt and BMP signaling pathways also trigger MuSK activation, possibly through direct binding of Wnt ligands and inhibitors to MuSK Fz-CRD or to LRP4 β-E domain clusters. The downstream effector functions differ into a spectrum that highlights numerous aneural regulatory events that could be particularly critical prior to motor neuron innervation and NMJ formation.