DOI: 10.25549/usctheses-c3-158968
title: Unraveling spatial precision In oligodendrocyte myelination: instruction without induction

description: All God’s creatures are subjected to natural selection, and evolutionary pressures have given rise to remarkable adaptive strategies designed for the survival of the fittest. For sophisticated nervous systems, the ability to respond quickly and appropriately to a complex array of external stimuli is essential. As such, myelin is a unique product of vertebrate evolution that serves to increase the conduction speed of neuronal signals in a space-efficient manner. Myelin consists of multiple compacted layers of lipid-rich plasma membrane wrapped helically around axons, which serves to insulate by increasing axonal membrane resistance and decreasing capacitance. Segments of myelin sheath, known as myelin internodes, are separated by nodes of Ranvier where voltage-gated sodium channels congregate. Myelinated axons are thus able to propagate signals rapidly in a saltatory fashion from node to node. ❧ During development, glial cells known as oligodendrocytes are responsible for forming myelin in the central nervous system (CNS). This is a spatially regulated process, whereby some axons are myelinated but not others, and a precise number of myelin internodes of appropriate length are generated and deposited along all relevant axons. How does the nervous system ensure that all relevant axons are myelinated perfectly? The presence of both myelinated and unmyelinated axons implies that the axon may provide instructions to the oligodendrocyte and dictate its own myelination status. Surprisingly, we find that a minimum fiber diameter threshold is causal and sufficient for the initiation of myelination, suggesting that the axon is purely permissive, and does not provide inductive cues to the oligodendrocyte for this purpose. However, with each individual oligodendrocyte capable of myelinating multiple axons, and multiple oligodendrocytes forming myelin internodes along a single axon, how do these cells coordinate the spatial deposition of myelin in the absence of axonal induction? As competition-based refinement mechanisms are often involved in the specific patterning of the nervous system, we hypothesize that neighboring oligodendroglia compete for available axon space, and underlying this competition is the capacity of oligodendrocytes to form varying number and length of myelin internodes. Here we show that the amino-terminal region of Nogo-A expressed by oligodendroglia is necessary and sufficient for inhibiting the generation of myelin internodes. Genetic deletion of Nogo results in exuberant and spatially expansive myelination during development, and Nogo knockout (KO) mice exhibit enhanced myelin repair after demyelination. ❧ Together, these findings reveal the unique ability of oligodendrocytes to initiate myelination and coordinate the generation of myelin internodes without axonal inductive cues. Instead, permissive and inhibitory mechanisms both contribute to the precise spatial patterning of oligodendrocyte myelination. Identifying therapeutic strategies that account for these mechanisms will provide valuable insight for myelin repair.