The scales and tales of myelination: using zebrafish and mouse to study myelinating glia

Abstract

Myelin, the lipid-rich sheath that insulates axons to facilitate rapid conduction of action potentials, is an evolutionary innovation of the jawed-vertebrate lineage. Research efforts aimed at understanding the molecular mechanisms governing myelination have primarily focused on rodent models; however, with the advent of the zebrafish model system in the late twentieth century, the use of this genetically tractable, yet simpler vertebrate for studying myelination has steadily increased. In this review, we compare myelinating glial cell biology during development and regeneration in zebrafish and mouse and enumerate the advantages and disadvantages of using each model to study myelination. This article is part of a Special Issue entitled SI: Myelin Evolution.

Keywords: Mouse; Myelin; Oligodendrocyte; Schwann cell; Zebrafish.

Figure 1

Schwann cell development. Descriptions follow above images from left to right. Neural crest (NC)/Schwann cell (SC) lineage cells are shown in blue, axons/neuronal tissues are shown in green, and maturing SC basal lamina is shown in orange. NC cells delaminate from the roof plate (RP) of the neural tube (shown in cross section) during embryonic development and migrate into the periphery where SC precursors are specified. SC precursors then co-migrate along growing axons as they pathfind (lateral view shown). Once this migration has ended, SC precursors transition into immature SCs, which surround bundles of axons, interdigitate cytoplasmic processes into the bundle, and sort the axons within by diameter in a process called radial sorting (these and all subsequent diagrams shown in cross section). Small caliber axons are sorted by non-myelinating, Remak SCs into a Remak bundle. Large caliber axon segments are sorted into a 1:1 relationship with a pro-myelinating SC; which, upon terminal differentiation signals, successively spirals its plasma membrane around the sorted axon to form myelin. Accompanying table shows the approximate age (hours post-fertilization (hpf) or embryonic day (E)) and key molecular markers for each stage of SC development in zebrafish and mouse. An “a” or a “b” following zebrafish markers indicates that the gene is duplicated in the zebrafish genome. We note that the ages indicated for zebrafish development refer specifically to the posterior lateral line nerve (pLLn) at a stereotyped position, between segments 5–7, along the anterior-posterior axis. FP, floor plate.

Figure 2

Basal lamina observations in zebrafish and mouse. (A–C) Representative transmission electron microscopy (TEM) images of cross sections through the pLLn in a 5 day post-fertilization (dpf) zebrafish larva (A-B’) and a 6 months post-fertilization (mpf) adult zebrafish (C). (A) The basal lamina (BL) is not readily detected around SCs (pseudocolored blue in all images) in the zebrafish pLLn during larval stages when the nerves are fixed well by microwave-assisted chemical techniques (e.g., Czopka and Lyons, 2011). (B-B’) Suboptimal fixation of the pLLn causes gaps between individual SCs such that the immature BL is detected (white arrowhead). (C) Mature BL can be more readily observed as an electron dense structure surrounding mature SCs at 6 mpf (red arrowheads). (D–E) Representative TEM images of cross-sections through mouse sciatic nerve at postnatal (P) day 3 (D) and P14 (E). At P3, immature BL (white arrowheads) is detected surrounding an immature SC as it sorts multiple axons (D). By P14, an electron dense, mature BL (red arrowheads) is seen surrounding a myelinating SC (E). Scale bars, 500 nm.

Figure 3

Peripheral myelin compaction. (A–D) Representative TEM images of cross sections through the pLLn in 3 dpf (A), 5 dpf (B), 21 dpf (C), and 6 mpf zebrafish to show myelin compaction during early larval, larval, juvenile, and adult stages of zebrafish development, respectively. Myelin appears as loose wraps (red arrowheads) through juvenile stages in zebrafish and does not fully compact until adulthood. We note that TEMs were obtained from animals processed by microwave-assisted chemical fixation methods (e.g., Czopka and Lyons 2011). (E–H) Representative TEM images of a cross-section through mouse sciatic nerve at P3, P14, P21, and P180. At all stages of development, mouse peripheral myelin appears fully compact. Scale bars, 1 µm.

Figure 4

Oligodendrocyte development. Descriptions follow above images from left to right. Neural precursor (NP)/oligodendrocyte (OL) lineage cells are shown in purple and axon/neuronal tissues are shown in green. NP cells born within the pMN domain of the embryonic neural tube (shown in cross-section) give rise to OL precursor cells (OPCs). OPCs proliferate as they migrate through the developing CNS (image and all subsequent images shown as lateral views). Following migration, OPCs transition into pre-myelinating OLs, which extend cytoplasmic processes towards and associate with axons, but do not yet form myelin. Upon terminal differentiation, pre-myelinating OLs become myelinating OLs and iteratively wrap their plasma membranes around multiple axon segments to form myelin sheaths. Accompanying table indicates approximate age in zebrafish (shown in hpf) and mouse (shown in embryonic (E) days) in addition to key molecular markers characteristic of each stage of OL development. An “a” or a “b” following zebrafish markers indicates that the gene is duplicated in the zebrafish genome. Ages indicated for zebrafish development refer specifically to the spinal cord at a stereotyped position along the anterior-posterior axis (between segments 5–7). RF, roof plate. FP, floor plate.