Abstract
Synaptogenesis requires orchestrated intercellular communication between synaptic partners, with trans-synaptic signals necessarily traversing the extracellular synaptomatrix separating presynaptic and postsynaptic cells. Extracellular matrix metalloproteinases (Mmps) regulated by secreted tissue inhibitors of metalloproteinases (Timps), cleave secreted and membrane-associated targets to sculpt the extracellular environment and modulate intercellular signaling. Here, we test the roles of Mmp at the neuromuscular junction (NMJ) model synapse in the reductionist Drosophila system, which contains just two Mmps (secreted Mmp1 and GPI-anchored Mmp2) and one secreted Timp. We found that all three matrix metalloproteome components co-dependently localize in the synaptomatrix and show that both Mmp1 and Mmp2 independently restrict synapse morphogenesis and functional differentiation. Surprisingly, either dual knockdown or simultaneous inhibition of the two Mmp classes together restores normal synapse development, identifying a reciprocal suppression mechanism. The two Mmp classes co-regulate a Wnt trans-synaptic signaling pathway modulating structural and functional synaptogenesis, including the GPI-anchored heparan sulfate proteoglycan (HSPG) Wnt co-receptor Dally-like protein (Dlp), cognate receptor Frizzled-2 (Frz2) and Wingless (Wg) ligand. Loss of either Mmp1 or Mmp2 reciprocally misregulates Dlp at the synapse, with normal signaling restored by co-removal of both Mmp classes. Correcting Wnt co-receptor Dlp levels in both Mmp mutants prevents structural and functional synaptogenic defects. Taken together, these results identify an Mmp mechanism that fine-tunes HSPG co-receptor function to modulate Wnt signaling to coordinate synapse structural and functional development.
Highlights
Development of a communicating junction between a presynaptic neuron and its postsynaptic target requires coordinated signaling between synaptic partner cells
Mmp1 and Mmp2 both regulate synapse morphogenesis We first asked whether the two Drosophila Matrix metalloproteinases (Mmps) affect morphological synaptogenesis at the well-characterized glutamatergic neuromuscular junction (NMJ)
Ubiquitous (UH1) mmpRNAi for both Mmp classes produced similar increases in bouton number compared with LOF mutants (Fig. 1B, cell-targeted mmpRNAi), with measured protein knockdown levels that were comparable to the corresponding mutants (Fig. S7)
Summary
Development of a communicating junction between a presynaptic neuron and its postsynaptic target requires coordinated signaling between synaptic partner cells. Received March 2015; Accepted November 2015 activate, sequester, release or expose cryptic sites, thereby sculpting the extracellular environment and modulating intercellular signaling (Kessenbrock et al, 2010; Page-McCaw et al, 2007; Sternlicht and Werb, 2001). 24 Mmps regulated by four Timps make genetic studies challenging, with extensive functional redundancy and compensation (Page-McCaw et al, 2007). In lieu of mammalian studies, which show that extracellular proteases play central roles determining synapse structure, function and number (reviewed in Reinhard et al, 2015; Shinoe and Goda, 2015; Wójtowicz et al, 2015), we took advantage of the reductionist Drosophila model to genetically dissect the complete, integrated mechanism of the matrix metalloproteome in synaptic development
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