Fig. 9: Site-directed vesicular trafficking and localized release of muscle-generated BDNF regulate AChR redistribution and clustering at developing NMJs in vitro and in vivo.

a In nerve-muscle cocultures, we speculate that PLSs direct the vesicular trafficking of not only MT1-MMP, but also BDNF and its precursor proBDNF for localized release at AChR clusters. The intracellular endoprotease furin mediates the proteolytic conversion of proBDNF to mBDNF for activating TrkB receptors in muscles. Knockdown of muscle BDNF expression affects aneural AChR cluster formation; therefore, less AChR molecules are redistributed and recruited for the assembly of nerve-induced synaptic AChR clusters. b At developing NMJs in vivo, MBKO mouse embryos exhibit reduced AChR prepatterning in the diaphragm muscles and reduced axonal branching and arborization in the phrenic nerves at E13.5. The defects in AChR prepatterning reduce the number of AChR molecules being redistributed to the postsynaptic apparatus, as reflected by the reduced intensity of synaptic AChR clusters in MBKO mice, at E18.5.