Neuronal activity drives FMRP- and HSPG-dependent matrix metalloproteinase function required for rapid synaptogenesis

Abstract

Matrix metalloproteinase (MMP) functions modulate synapse formation and activity-dependent plasticity, with MMP dysfunction implicated in Fragile X syndrome (FXS), a disease caused by the loss of the RNA binding protein FMRP and characterized by neurological dysfunction and intellectual disability. Gene expression studies in Drosophila suggest that Mmps cooperate with the heparan sulfate proteoglycan (HSPG) glypican co-receptor Dally-like protein (Dlp) to restrict trans-synaptic Wnt signaling, and that synaptogenic defects in the fly model of FXS are alleviated by both Mmp inhibition and Dlp genetic reduction. Here, we used the Drosophila neuromuscular junction (NMJ) glutamatergic synapse to test activity-dependent Dlp and Mmp intersections in the context of FXS. We found that rapid, activity-dependent synaptic bouton formation was dependent upon secreted Mmp1. Acute neuronal stimulation reduced Mmp2 abundance, but increased that of both Mmp1 and Dlp as well as Dlp and Mmp1 co-localization at the synapse. Dlp function bidirectionally controlled Mmp1 abundance, localization and proteolytic activity around synapses. Dlp glycosaminoglycan (GAG) chains mediated this functional interaction with Mmp1. In the FXS fly model, activity-dependent increases in Mmp1 abundance and activity were lost but were restored by reducing the amount of synaptic Dlp. These data indicate that neuronal activity-induced, HSPG-dependent Mmp regulation drives activity-dependent synaptogenesis, and that this is impaired in FXS. Thus exploring this mechanism further may reveal therapeutic targets with potential to restore synaptogenesis in FXS patients.

Carrier of Wingless (Cow) Regulation ofDrosophilaNeuromuscular Junction Development

“…In the developing wing disk, the Wnt Wg is produced in a stripe of cells at the dorsal/ventral margin boundary, and acts as an intercellular morphogen through Fz2 receptor signaling (Bhanot et al, 1996;Zecca et al, 1996;Neumann and Cohen, 1997). The glypican HSPGs Dally and Dlp, bound to outer plasma membrane leaflets via GPI anchors, bind Wg to regulate both ligand distribution and intercellular signaling (Tsuda et al, 1999;Baeg et al, 2001;Dear et al, 2017). It has been proposed that Dally/Dlp HSPGs are involved in the movement of extracellular Wg to form a morphogen gradient (Han et al, 2005).…”

“…Cow could be considered an alternative extracellular Wg transport method (Chang and Sun, 2014), acting to shield Wg while facilitating transport through the extracellular synaptomatrix Dear et al, 2016). In addition, HSPGs have been shown to regulate ligands by stabilizing, degrading, or sequestering the ligand, or as bifunctional coreceptors, or as facilitators of transcytosis (Lin, 2004;Dear et al, 2017). Results presented here are consistent with the hypothesis that Cow is mediating Wg transport across the NMJ synapse (Chang and Sun, 2014), but also that Cow has an additional role in the negative regulation of Wg synaptic signaling.…”

“…Drosophila NMJ analyses have begun to more systematically elucidate HSPG roles in NMJ formation and function (Ren et al, 2009;Kamimura and Maeda, 2017). In particular, the glypican HSPG Dlp regulates Wg signaling to modulate both NMJ structure and function, including the regulation of active zone formation and SV release (Johnson et al, 2006;Friedman et al, 2013;Dear et al, 2017). Wg binds the core Dlp, with HS chains enhancing this binding, to retain Wg on the cell surface, where it can both compete with Fz2 receptors and facilitate Wg-Fz2 binding (Yan et al, 2009).…”

MMPs and ADAMs in neurological infectious diseases and multiple sclerosis

“…As shown in Table 1, this overly simplistic concept has been revised in recent years, as the effects of MMPs on ECM metabolism are not only of destructive character, but includes as well reparative functions, depending on the phase of MS. MMP-9 is involved in oligodendrocyte regrowth [203], while MMP-7 cleaves remyelination-impairing fibronectin to allow remyelination, and the authors speculate that a too low MMP-7 level contributes to the persistence of demyelination in chronic MS lesions and prevents oligodendrocyte maturation [204]. A further function of MMPs for synaptogenesis has been recognized [205,206]. These findings are relevant for the concept how MMP inhibition could be used as therapeutic approach in MS.…”

The HSPG Glypican Regulates Experience-Dependent Synaptic and Behavioral Plasticity by Modulating the Non-Canonical BMP Pathway

“…It remains unclear how octopamine signaling at type I synaptic regions regulates postsynaptic Dlp levels. Broadie and collaborators revealed that ECM metalloproteinases (Mmp1 and Mmp2) and the tissue inhibitor of metalloproteinases (Timp) play critical roles in synapse formation and activity-dependent plasticity in the Drosophila NMJ (Dear et al, 2016(Dear et al, , 2017Shilts and Broadie, 2017). Mmp2 from the presynaptic and postsynaptic compartments has been shown to negatively regulate synaptic Dlp levels at the NMJ, possibly by the proteolytic cleavage of Dlp core proteins (Wang and Page-McCaw, 2014).…”