Somatodendritic Expression of JAM2 Inhibits Oligodendrocyte Myelination

•Neuronal JAM2 is necessary and sufficient to inhibit myelination•JAM2 knockout mice exhibit aberrantly myelinated neuronal cell bodies•Myelinated neuronal cell bodies are distinctly PAX2+ inhibitory interneurons•Oligodendrocytes utilize non-axonal inhibitory signaling in myelination

SummaryMyelination occurs selectively around neuronal axons to increase the efficiency and velocity of action potentials. While oligodendrocytes are capable of myelinating permissive structures in the absence of molecular cues, structurally permissive neuronal somata and dendrites remain unmyelinated. Utilizing a purified spinal cord neuron-oligodendrocyte myelinating co-culture system, we demonstrate that disruption of dynamic neuron-oligodendrocyte signaling by chemical cross-linking results in aberrant myelination of the somatodendritic compartment of neurons. We hypothesize that an inhibitory somatodendritic cue is necessary to prevent non-axonal myelination. Using next-generation sequencing and candidate profiling, we identify neuronal junction adhesion molecule 2 (JAM2) as an inhibitory myelin-guidance molecule. Taken together, our results demonstrate that the somatodendritic compartment directly inhibits myelination and suggest a model in which broadly indiscriminate myelination is tailored by inhibitory signaling to meet local myelination requirements.