Matrix Metalloproteinase Requirements for Neuromuscular Synaptogenesis

Abstract

Synaptogenesis requires coordinated intercellular communication between a presynaptic neuron and postsynaptic target cell. Neural development and maintenance is driven by a wide variety of molecules that necessarily traverse the specialized extracellular synaptomatrix separating partner cells. Extracellular matrix metalloproteinases (Mmps) shape the synaptomatrix environment and aberrant upregulation of Mmp function is causally linked to Fragile X syndrome (FXS), the most common heritable form of autism spectrum disorder and related intellectual disability. Therefore, researchers are interested in understanding how Mmps are regulated and function in the synaptomatrix to influence synaptogenesis and how this relates to the FXS synaptic disease state. A well-established Drosophila neuromuscular junction (NMJ) model system, containing just two conserved Mmps (Mmp1 and Mmp2), was used to fully interrogate Mmp functions in normal synapse development and in relationship to the FXS disease state. Synaptic Mmp1 and Mmp2 expression was co-dependently regulated and Mmp1 and Mmp2 co-suppressed each other’s synaptogenic requirements. Differential Mmp regulation of heparan sulfate proteoglycan (HSPG), Dally-like protein (Dlp)-dependent intercellular Wnt signaling was found to restrict structural and functional NMJ development. A reciprocal Dlp-Mmp1 interaction was identified that localizes Mmp1 function in the synaptomatrix. This identified mechanism also causes aberrant Mmp1 upregulation in the FXS disease state which is thought to be causal for synaptogenic defects characterizing FXS.