UCSF

The advent of myelin was instrumental in advancing the nervous system during vertebrate evolution. With more rapid and efficient communication between neurons, faster and more complex computation could be performed in a given time and space. Our knowledge of how myelin-forming oligodendrocytes select and wrap axons has been limited by insufficient spatial and temporal resolution. By virtue of recent technological advances, significant progress has clarified longstanding controversies in the field. Here, we review insights into myelination, from target selection to axon wrapping and membrane compaction, and discuss how understanding these processes has unexpectedly opened new avenues of insight into myelination-centered mechanisms of neural plasticity.

Myelination 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 coculture system, we demonstrate that disruption of dynamic neuron-oligodendrocyte signaling by chemical crosslinking 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.

Efficient myelin repair after demyelinating injury is thought to prevent loss of neural function and prevent neurodegeneration. Within the central nervous system, the capacity for myelin repair theoretically exists. Oligodendrocyte precursor cells (OPCs) are capable of differentiating into myelinating oligodendrocytes throughout life. However, many demyelinated lesions fail to remyelinate, despite the presence of OPCs and even differentiated oligodendrocytes within demyelinated areas. It has been recently shown that more efficient myelin debris removal promotes remyelination. Myelin guidance molecules at work during development to ensure correct myelination patterns, like inhibitory JAM2, may play significant roles in preventing efficient myelin repair in disease. Identifying more myelin guidance molecules may represent a novel avenue to develop new remyelination therapies.