| Abstract No.: | A-A1022 |
| Country: | Canada |
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| Title: | NOGO-66 RECEPTOR 1 SHEDDING IN THE CENTRAL NERVOUS SYSTEM |
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| Authors/Affiliations: | 1 Gino B. Ferraro*; 1 Alyson E. Fournier;
1 Montreal Neurological Institute, McGill University;
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| Content: | Background: The adult mammalian central nervous system is characterized by poor regeneration after injury. This has been attributed to both the glial scar and myelin debris. Myelin-associated inhibitors (MAIs) can activate the Nogo-66 receptor 1 (NgR1) expressed by neurons and mediate growth inhibition. Cell surface expression of NgR1 can be regulated by membrane-type matrix metalloproteinase (MT-MMP)-dependent cleavage, a process termed shedding. Enhanced NgR1 shedding may be an effective strategy to decrease the sensitivity of neurons to myelin.
Objective: Identify MT-MMPs responsible for NgR1 shedding and determine their role in regulating neuronal outgrowth on inhibitory CNS substrates.
Materials and Methods: Shed NgR1 from cell lines and neuronal cultures was collected from concentrated media and detected by Western blotting. Overexpression of MT-MMPs was evaluated for effects on NgR1 shedding and on neurite outgrowth.
Results: We demonstrate that NgR1 can be shed from several CNS tissues including cerebral cortex, hippocampus and brain stem. We have examined cell surface NgR1 cleavage in transfected neuroblastoma cells and primary neurons. We find that NgR1 shedding is a property of multiple neuronal cell types including neuroblastoma cells, dorsal root ganglion neurons and cerebellar neurons. Expression profiling indicates that neurons express multiple MT-MMPs. Further, we find that NgR1 shedding is regulated by overexpression of specific MT-MMPs.
Conclusion:
NgR1 shedding occurs throughout the CNS. Several MT-MMPs might be responsible for this process. We propose that NgR1 shedding in the CNS regulates its activity and MT-MMP up-regulation could attenuate neuronal responses to MAIs.
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