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J Neurosci. 2018 Jan 17;38(3):518-529. doi: 10.1523/JNEUROSCI.0962-17.2017. Epub 2017 Dec 1.

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

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Department of Neurology and Neurosurgery, Montréal Neurological Institute, Rue University, Montréal, Québec H3A 2B4, Canada.
Centre for Research in Neuroscience, Department of Neurology and Neurosurgery, The Research Institute of the McGill University Health Centre, Montreal General Hospital, Montréal, Québec H3G 1A4, Canada.
Department of Psychiatry and Neuroscience, Université Laval, CERVO Brain Research Centre, Québec, Québec G1V 0A6, Canada, and.
Craniofacial and Skeletal Diseases Branch, NIDCR, National Institutes of Health (NIH), Bethesda, Maryland 20892-4380.
Department of Neurology and Neurosurgery, Montréal Neurological Institute, Rue University, Montréal, Québec H3A 2B4, Canada,


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 vivo 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 vivo Together, our findings support a role for MT3-MMP-dependent shedding of NgR1 in regulating excitatory synapse development.SIGNIFICANCE STATEMENT 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.


Nogo receptor; metalloproteinase; synaptogenesis

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