Advances in myelinating glial cell development

Abstract

In the vertebrate nervous system, the fast conduction of action potentials is potentiated by the myelin sheath, a multi-lamellar, lipid-rich structure that also provides vital trophic and metabolic support to axons. Myelin is elaborated by the plasma membrane of specialized glial cells, oligodendrocytes in the central nervous system (CNS) and Schwann cells (SCs) in the peripheral nervous system (PNS). The diseases that result from damage to myelin or glia, including multiple sclerosis and Charcot-Marie-Tooth disease, underscore the importance of these cells for human health. Therefore, an understanding of glial development and myelination is crucial in addressing the etiology of demyelinating diseases and developing patient therapies. In this review, we discuss new insights into the roles of mechanotransduction and cytoskeletal rearrangements as well as activity dependent myelination and axonal maintenance by glia. Together, these discoveries advance our knowledge of myelin and glia in nervous system health and plasticity throughout life.

Figure 1

Mechanotransduction plays a critical role in SC development and differentiation. Immature SCs migrate and divide along growing axons. The forces associated with migration are thought to activate the mechanotransducers YAP/TAZ in SC cytoplasm, which then translocate to the nucleus where they interact with the TEAD family transcription factors to drive expression of important myelin genes (a). After SCs have formed a “1:1” relationship with axons in the pro-myelinating stage, maturation of the basal lamina and subsequent polymerization of Laminin-211 is thought to activate GPR126, which initiates a transcriptional cascade activating Oct6 and promoting myelination (b). Eventually, SCs wrap myelin around axon segments to form internodes (c).

Figure 2

Multiple factors fine tune the myelination potential of oligodendrocytes. Oligodendrocytes preferentially myelinate electrically active axons (a) and retract processes from inactive axons (b). Furthermore, the intrinsic myelination program is moderated by negative regulators, such as JAM2, which are expressed on dendrites (c). Vesicular release from active axons initiates a cascade of events, one of which is the translation of locally transported Mbp mRNA. MBP then competes with the factors gelsolin and cofilin for binding to PIP2 on the inner oligodendrocyte membrane, resulting in release of the two proteins and subsequent actin disassembly (d). During wrapping, filamentous actin is located at the leading edge of the inner tongue and is proposed to propel the membrane forward by actin disassembly (e) (image adapted from Nawaz et al. 2015).

Figure 3

Comparing and contrasting SC and oligodendrocyte development and differentiation. Although both SCs and oligodendrocytes produce the myelin critical for nervous system function, there are important differences in the mechanisms by which they generate myelin. The similarities and differences between SCs and oligodendrocytes discussed in this review are summarized in the table above.