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Schwann cell development: From neural crest to myelin sheath

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Abstract Vertebrate nervous system function requires glial cells, including myelinating glia that insulate axons and provide trophic support that allows for efficient signal propagation by neurons. In vertebrate peripheral nervous systems, neural crest‐derived glial cells known as Schwann cells (SCs) generate myelin by encompassing and iteratively wrapping membrane around single axon segments. SC gliogenesis and neurogenesis are intimately linked and governed by a complex molecular environment that shapes their developmental trajectory. Changes in this external milieu drive developing SCs through a series of distinct morphological and transcriptional stages from the neural crest to a variety of glial derivatives, including the myelinating sublineage. Cues originate from the extracellular matrix, adjacent axons, and the developing SC basal lamina to trigger intracellular signaling cascades and gene expression changes that specify stages and transitions in SC development. Here, we integrate the findings from in vitro neuron–glia co‐culture experiments with in vivo studies investigating SC development, particularly in zebrafish and mouse, to highlight critical factors that specify SC fate. Ultimately, we connect classic biochemical and mutant studies with modern genetic and visualization tools that have elucidated the dynamics of SC development. This article is categorized under: Signaling Pathways > Cell Fate Signaling Nervous System Development > Vertebrates: Regional Development
Neural crest‐derived Schwann cells form myelin in the peripheral nervous system. (a) Stepwise developmental stages of Schwann cells from neural crest to myelinating glia, shown in cross‐section. Glial cells and precursors are indicated in green; neurons and their axons are marked in blue. Associated timepoints for developmental stages are given in hours post‐fertilization (hpf) for zebrafish and embryonic day (E) for mice (Ackerman & Monk, 2016 ). Neural crest cells delaminate from the neural tube to migrate along axons as Schwann cell precursor cells. These glial precursors transition to immature Schwann cells that sample the axon bundle via cytoplasmic extensions and ultimately select a single axon segment to encompass in a process called radial sorting. The promyelinating Schwann cells then wrap the axon segment to form the myelin sheath. (b) Key features of a maturing peripheral myelin sheath, shown in cross section with the exception of Schmidt‐Lanterman incisures (panel, longitudinal). Non‐compact myelin is found immediately adjacent to the axon (adaxonal), around the nucleus and in Cajal bands on the abaxonal surface, and in Schmidt‐Lanterman incisures that run radially through the myelin sheath
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Key pathways driving radial sorting and myelination in Schwann cells. (a–d) Ligand–receptor interactions with axons (blue, represented in cross‐section) and with components of the developing basal lamina on the abaxonal surface (yellow) affect signal transduction and transcriptional regulation (green ovals, depicted in nucleus) in developing Schwann cells. For clarity, only distinguishing markers and representative members of pathways are shown. (a) Immature Schwann cells initiate radial sorting via interactions with NRG1 on axons and laminins in the basal lamina. Large caliber axons are sorted into a 1:1 relationship with the developing Schwann cell. (b) A subset of Schwann cells adopt a non‐myelinating fate, such as terminal Schwann cells that support neuromuscular junctions or as Remak Schwann cells that encompass multiple smaller caliber axons. (c) Promyelinating Schwann cells have sorted an axon segment and begin the transition to wrapping. Maturation of the basal lamina drives GPR126 signaling, and NRG1 on axons dictate extent of myelination. (d) Signaling via GPR126 and NRG1/ERBB2/3 drive elaboration of the myelin sheath, while transcriptional regulation via epigenetic modifications supports commitment to myelinating glial cell fate
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Key pathways driving Schwann cell precursors to immature Schwann cells. Ligand–receptor interactions with axons (blue, represented in cross‐section) and transcriptional regulation (green ovals, depicted in nucleus) in Schwann cell precursors within the myelinating lineage. For clarity, only distinguishing markers and representative members of pathways are shown. Immature Schwann cells are committed to the Schwann cell fate and begin to deposit a basal lamina (yellow)
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Peripheral glial cells, including myelinating glia, are derived from neural crest precursor cells. (a) Cross‐section of neural crest delamination in early development. Sonic hedgehog (SHH) from the notochord (orange) is critical for specifying the ventral neural tube (blue) and somitic mesoderm (pink). At the dorsal neural tube, neural crest precursor cells (green) delaminate from the dorsal neural tube to migrate along somitic mesoderm and ultimately associate with axons. (b) Key pathways in migratory neural crest that drive glial fate. Solid vertical arrowheads denote increased expression to promote development to the next stage; open arrows denote positive regulation. Transcriptional regulators are shown in the nucleus. (c) Derivatives of neural crest cells, including the Schwann cell lineage through Schwann cell precursors (top) and other non‐myelinating lineages (bottom). In all schematics, glial cells are green and neurons/axons are blue. While SCPs serve as progenitors for SC sublineages, SCPs may serve as progenitors for other neural crest derived peripheral glia including enteric glia (dotted arrow)
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