Podosome-directed MT1-MMP trafficking and surface insertion regulate AChR clustering & remodeling

Abstract

At vertebrate neuromuscular junctions (NMJs), the basal lamina in the synaptic cleft contains different extracellular matrix (ECM) proteins that induce and maintain synaptic specializations. Local modulation of ECM environment is believed to regulate synaptic formation and plasticity. In this study, we first report that ECM-induced podosome-like structures (PLSs) cause ECM degradation focally at perforated acetylcholine receptor (AChR) clusters in primary muscle cultures. Mechanistically, intracellular trafficking and surface insertion of membrane-type 1 matrix metalloproteinase (MT1-MMP) are targeted to PLSs enriched at AChR clusters through end-binding protein 1 (EB1)/cytoplasmic linker associated protein (CLASP)-mediated microtubule-capturing mechanisms, which in turn control the assembly and stability of AChR clusters. Upon synaptic induction, we further identify a differential role of MT1-MMP in regulating the formation of synaptic AChR clusters and the dispersal of aneural AChR clusters. Collectively, this study reveals that PLS-directed vesicular trafficking and surface insertion of MT1-MMP modulate local ECM environment during the formation, topological remodeling, and re-distribution of AChR clusters at developing NMJs.