MT3-MMP Promotes Excitatory Synapse Formation by Promoting Nogo-66 Receptor Ectodomain Shedding.

TitleMT3-MMP Promotes Excitatory Synapse Formation by Promoting Nogo-66 Receptor Ectodomain Shedding.
Publication TypeJournal Article
Year of Publication2018
AuthorsSanz, RL, Ferraro, GB, Kacervosky, J, Salesse, C, Gowing, E, Hua, L, Rambaldi, I, Beaubien, F, Holmbeck, K, Cloutier, JF, Lévesque, M, Murai, K, Fournier, AE
JournalJ Neurosci
Volume38
Issue3
Pagination518-529
Date Published2018 Jan 17
ISSN1529-2401
Abstract

Cell-surface molecules are dynamically regulated at the synapse to assemble and disassemble adhesive contacts that are important for synaptogenesis and for tuning synaptic transmission. Metalloproteinases dynamically regulate cellular behaviors through the processing of cell surface molecules. In the present study, we evaluated the role of membrane-type metalloproteinases (MT-MMPs) in excitatory synaptogenesis. We find that MT3-MMP and MT5-MMP are broadly expressed in the mouse cerebral cortex and that MT3-MMP loss-of-function interferes with excitatory synapse development in dissociated cortical neurons and in We identify Nogo-66 receptor (NgR1) as an MT3-MMP substrate that is required for MT3-MMP-dependent synapse formation. Introduction of the shed ectodomain of NgR1 is sufficient to accelerate excitatory synapse formation in dissociated cortical neurons and in Together, our findings support a role for MT3-MMP-dependent shedding of NgR1 in regulating excitatory synapse development. In this study, we identify MT3-MMP, a membrane-bound zinc protease, to be necessary for the development of excitatory synapses in cortical neurons. We identify Nogo-66 receptors (NgR1) as a downstream target of MT3-MMP proteolytic activity. Furthermore, processing of surface NgR1 by MT3-MMP generates a soluble ectodomain fragment that accelerates the formation of excitatory synapses. We propose that MT3-MMP activity and NgR1 shedding could stimulate circuitry remodeling in the adult brain and enhance functional connectivity after brain injury.

DOI10.1523/JNEUROSCI.0962-17.2017
Alternate JournalJ. Neurosci.
PubMed ID29196321