An underappreciated aspect of myelination is the avoidance of selecting non-axonal targets. Oligodendrocytes (OLs) select axons while avoiding neuronal somata, dendrites and processes of other glial cells. How is this specificity accomplished? While OLs are capable of myelinating permissive structures (artificial fibers and beads) in the absence of molecular cues, structurally permissive neuronal somata and dendrites remain unmyelinated. These observations suggest that myelin substrate selection is not cell-intrinsically limited to physiologically relevant geometries. OL cell processes are likely sensitive to cell-extrinsic cues that ensure the selection of axons with high fidelity. Utilizing a novel purified spinal cord neuron-OL myelinating coculture system we find that disruption of dynamic neuron-OL signaling by chemical crosslinking results in aberrant myelination of the somatodendritic compartment of neurons. In this proposal, we hypothesize that inhibitory somatodendritic cues act as repulsive membrane signals that are necessary and sufficient to prevent non-axonal myelination. In this proposal we will: 1. Perform next-generation sequencing and candidate profiling of membrane proteins expressed exclusively in purified spinal cord neurons. 2. Identify, confirm and validate expression and localization of repulsive membrane proteins enriched in the somatodendritic compartment. 3. Investigate the necessity and sufficiency of the repulsive signal(s) to prevent aberrant myelination and identify receptor(s) on OPCs that mediate the inhibition. Our preliminary data identifies the Junctional Adhesion Molecule 2 (JAM2), expressed on the somata and dendrites of spinal cord neurons, as a repulsive signal that inhibits aberrant oligodendrocyte myelination. Taken together, we propose a model in which broadly indiscriminate myelination is tailored by inhibitory signaling to meet local myelination requirements.
An underappreciated aspect of myelination is the avoidance of selecting non-axonal targets--oligodendrocytes select axons while avoiding neuronal somata, dendrites and processes of other glial cells. Utilizing a novel purified spinal cord neuron-OL myelinating coculture system we find that disruption of dynamic neuron-OL signaling by chemical crosslinking results in aberrant myelination of the somatodendritic compartment of neurons. Our proposal will not only identify the inhibitory somatodendritic cues that are necessary and sufficient to prevent non-axonal myelination but will provide insight into a model which describes indiscriminate myelination tailored by inhibitory signaling to meet local myelination requirements.
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