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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS097428-03
Application #
9447242
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Morris, Jill A
Project Start
2016-06-01
Project End
2021-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Pan, Simon; Chan, Jonah R (2017) Regulation and dysregulation of axon infrastructure by myelinating glia. J Cell Biol 216:3903-3916
Bang, Marie L; Vainshtein, Anya; Yang, Hyun-Jeong et al. (2017) Glial M6B stabilizes the axonal membrane at peripheral nodes of Ranvier. Glia :
Osso, Lindsay A; Chan, Jonah R (2017) Architecting the myelin landscape. Curr Opin Neurobiol 47:1-7
Redmond, Stephanie A; Mei, Feng; Eshed-Eisenbach, Yael et al. (2016) Somatodendritic Expression of JAM2 Inhibits Oligodendrocyte Myelination. Neuron 91:824-836