Secreted tissue inhibitor of matrix metalloproteinase restricts -synaptic signaling to coordinate synaptogenesis.

Synaptogenesis is coordinated by -synaptic signals that traverse the specialized synaptomatrix between presynaptic and postsynaptic cells. Matrix metalloproteinase (Mmp) activity sculpts this environment, balanced by secreted tissue inhibitors of Mmp (Timp). Here, we use the simplified matrix metalloproteome to test the consequences of eliminating all Timp regulatory control of Mmp activity at the neuromuscular junction (NMJ). Using zymography, we find Timp limits Mmp activity at the NMJ terminal and shapes extracellular proteolytic dynamics surrounding individual synaptic boutons. In newly generated null mutants, NMJs exhibit architectural overelaboration with supernumerary synaptic boutons. With cell-targeted RNAi and rescue studies, we find that postsynaptic Timp limits presynaptic architecture. Functionally, null mutants exhibit compromised synaptic vesicle cycling, with activity that is lower in amplitude and fidelity. NMJ defects manifest in impaired locomotor function. Mechanistically, we find that Timp limits BMP -synaptic signaling and the downstream synapse-to-nucleus signal transduction. Pharmacologically restoring Mmp inhibition in null mutants corrects bone morphogenetic protein (BMP) signaling and synaptic properties. Genetically restoring BMP signaling in null mutants corrects NMJ structure and motor function. Thus, Timp inhibition of Mmp proteolytic activity restricts BMP -synaptic signaling to coordinate synaptogenesis.