Neurons Regulate Glial Cell Surface Proteome (P07.089)

Abstract

Objective: To identify glial cell surface receptors that transduce neuronal signals across glial plasma membrane. Background Bidirectional neuro-glia interactions are known to play important roles in maintaining normal functioning and architecture of CNS in health and disease. For example, neuronal signals reportedly influence overall gene expression in glial cells, but how these signals are transduced at the glial cell surface into glial specific functional responses remains undefined. Design/Methods: To identify receptors important in transducing neuro-glial communication, we performed a proteome screen on glial surface-enriched molecules obtained from primary glia, exposed to soluble neuronal factors or left un-treated as control. Results: While levels of proteins in the total glial cell lysates remained unchanged, cell surface biotinylation, followed by unbiased proteomics, identified significant changes in key signaling and adhesion molecules. Surprisingly, we observed that exposure to the neuronal factors caused contrasting regulation of several key molecules on the surface of astrocytes compared to oligodendrocytes, including adhesion molecules like N-cadherin and β-catenin along with neurotrophin receptors, known to positively regulate myelination. These molecules were strongly down-regulated on astrocytic surface whereas they were significantly up-regulated on oligodendrocytes. Consistent with the changes in expression of receptors, we found presence of secreted neurotrophins and processed N-cadherin ecto-domain in the neuronal media. We are now confirming that shed ecto-domain of N-cadherin and neurotrophins released by neurons can modulate cell surface expression of their receptors in a cell type specific manner, leading to different downstream activation events in distinct CNS glia. Conclusions: The distinct regulation of above mentioned cell surface receptors will be important in understanding the neuron-glial interactions in both normal development and neurological disorders. We hypothesise that normal neuro-glial cross talk is disrupted under inflamed CNS conditions; and understanding the mechanism of such a perturbed cellular communication is the subject of our ongoing studies. Disclosure: Dr. Awasthi has nothing to disclose. Dr. Morisse has nothing to disclose. Dr. Colman has nothing to disclose. Dr. Dhaunchak has nothing to disclose. Dr. Bar-Or has received personal compensation for activities with Aventis Pharmaceuticals, Bayhill Therapeutics, Biogen Idec, Berlex Laboratories, Eli Lilly & Company, Genentech, Inc., GlaxoSmithKline, Ono Pharmaceutical, Diogenix, Roche Diagnostics Corporation, Merck Serono, Novartis, Teva Neuroscience.