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. 2017 Mar 1;10:54. doi: 10.3389/fnmol.2017.00054

Figure 4.

Figure 4

Lrp4 and APP interaction during neuromuscular junction (NMJ) formation. Illustration depicting the interaction of Lrp4, MuSK, Agrin and APP/APLP1/APLP2 in the formation of the NMJ. Agrin binds Lrp4 resulting in phosphorylation (P) of MuSK, which leads to the recruitment and clustering of acetylcholine receptors (AchRs). The recruitment of AChR to the NMJ depends on all components of the complex. Knockouts of Lrp4, MuSK, Agrin, or APP/APLP1/APLP2 result in defective NMJ formation and perinatal lethality. APP and its family members (APLP1 and APLP2) have redundant functions, allowing them to compensate if one is knocked out. APLP1 is expressed on the presynaptic motor neuron, whereas APLP2 and APP are expressed by both nerve cells and muscle cells. Double knockouts lacking both APP and APLP1 form functional NMJs and are viable, whereas APP−/−/APLP2−/− and APLP1−/−/APLP2−/− mice have severely defective neuromuscular synapses and high postnatal lethality, indicating that APLP2 is an essential component in NMJ formation, but APP and APLP1 together can partially compensate in the absence of APLP2. Agrin is expressed in both neurons and muscle cells, but each express different isoforms. Isoforms expressed by neurons differ from muscular Agrin by the Z+ splice insert (yellow star), required for Lrp4 binding (Zong et al., 2012) and NMJ-formation (Burgess et al., 1999). In addition, besides secreted Agrin, motorneurons express a TM Agrin, which is not required for NMJ-formation. Extracellular cleavage of Agrin (α- and β-sites) can be mediated by Neurotrypsin and other as-yet unidentified proteases (black) expressed at the muscle. While Agrin cleavage is required for proper NMJ maturation, Neurotrypsin-mediated cleavage of Agrin is not—despite the fact that Neurotrypsin overexpression leads to NMJ-failures (Bolliger et al., 2010). The small soluble Z+ containing C-terminal fragment (after β-cleavage) is sufficient to bind Lrp4 and induce AChR-clustering, but it is less efficient compared to full length Agrin or Agrin cleaved at the α-site, only (Zong et al., 2012).