Diversity Matters: A Revised Guide to Myelination

Abstract

The evolutionary success of the vertebrate nervous system is largely due to a unique structural feature--the myelin sheath, a fatty envelope that surrounds the axons of neurons. By increasing the speed by which electrical signals travel along axons, myelin facilitates neuronal communication between distant regions of the nervous system. We review the cellular and molecular mechanisms that regulate the development of myelin as well as its homeostasis in adulthood. We discuss how finely tuned neuron-oligodendrocyte interactions are central to myelin formation during development and in the adult, and how these interactions can have profound implications for the plasticity of the adult brain. We also speculate how the functional diversity of both neurons and oligodendrocytes may impact on the myelination process in both health and disease.

Keywords: brain plasticity; cerebral cortex; development; myelin; neuron–glia interaction; oligodendrocytes.

Figure 1. Intrinsic and neuron-derived factors controlling oligodendrocyte development

Oligodendrocytes originate from pools of progenitors (OPCs) located in different regions of the developing CNS. After specification, OPCs spread throughout the CNS and eventually differentiate into pre-myelinating oligodendrocytes (Pre-OLs). Pre-OLs then produce large amounts of cell membrane, which wraps around multiple axons to form the myelin sheath (Myelinating oligodendrocytes). Several cell-autonomous factors that control one or more steps along this process have been identified; these include transcription factors, chromatin remodeling proteins and non-coding RNAs. In addition to these intrinsic factors, neuron-derived signals also play an active role in oligodendrocyte development and myelination. Among them, membrane-associated proteins, soluble factors and extracellular matrix proteins are involved in the positive or negative regulation of different stages of development, including proliferation, differentiation and initiation of myelination. Recent studies have also demonstrated that electrical activity of the axon can dramatically affect oligodendrocyte development and myelination in the CNS.

Figure 2. The “lumpers” and “splitters” dichotomy of oligodendrocyte cellular diversity

It is widely accepted that the nervous system is composed of many different classes of neurons, each with specific identities typically defined by structural, molecular and functional traits; these classes populate different regions and connect different areas of the nervous system. Conversely, oligodendrocytes are still considered by many as one homogeneous population (A, the lumpers); however, it is possible that structurally and functionally distinct subtypes exist (B, the splitters); these subtypes may have different myelinogenic potential and may also interact differently with neighboring neurons. Further investigation of oligodendrocyte diversity will be critical to better understand subtype-specific functions and neuron-glia interactions in the context of myelin formation and maintenance.

Figure 3. Developmental and adaptive myelination in the human brain

(A) Human myelination is mostly a postnatal process that peaks during childhood and can continue until early adulthood. (B) Once myelination of all brain regions is completed, production of new myelin is still possible; adults who actively learn complex tasks like studying a second language, juggling or piano-playing, show increased myelination in specific regions of the brain. These observations suggest that brain activity can impact the production of new myelin even in adulthood.