Río‐Hortega's drawings revisited with fluorescent protein defines a cytoplasm‐filled channel system of CNS myelin

Abstract

A century ago this year, Pío del Río‐Hortega (1921) coined the term ‘oligodendroglia’ for the ‘interfascicular glia’ with very few processes, launching an extensive discovery effort on his new cell type. One hundred years later, we review his original contributions to our understanding of the system of cytoplasmic channels within myelin in the context of what we observe today using light and electron microscopy of genetically encoded fluorescent reporters and immunostaining. We use the term myelinic channel system to describe the cytoplasm‐delimited spaces associated with myelin; being the paranodal loops, inner and outer tongues, cytoplasm‐filled spaces through compact myelin and further complex motifs associated to the sheath. Using a central nervous system myelinating cell culture model that contains all major neural cell types and produces compact myelin, we find that td‐tomato fluorescent protein delineates the myelinic channel system in a manner reminiscent of the drawings of adult white matter by Río‐Hortega, despite that he questioned whether some cytoplasmic figures he observed represented artefact. Together, these data lead us to propose a slightly revised model of the ‘unrolled’ sheath. Further, we show that the myelinic channel system, while relatively stable, can undergo subtle dynamic shape changes over days. Importantly, we capture an under‐appreciated complexity of the myelinic channel system in mature myelin sheaths.

Developmental Cues and Molecular Drivers in Myelinogenesis: Revisiting Early Life to Re-Evaluate the Integrity of CNS Myelin

“…Rudolf Virchow initially designated the term “myelin” in 1854, named after the Greek word “marrow” (myelos), since it is especially plentiful in the brain’s center, or marrow [ 6 ]. He posited that neurons produced myelin, but Pío del Río Hortega’s better histological staining processes almost a century ago revealed that myelin is created by specific glial cells, which are OLs [ 7 , 8 ].…”

CNS myelination requires VAMP2/3-mediated membrane expansion in oligodendrocytes

“…The copyright holder for this preprint (which this version posted July 10, 2022. ; https://doi.org/10.1101/2022.07.08.498895 doi: bioRxiv preprint receptor (SNARE) complexes, where vesicular SNARE proteins (v-SNAREs) pair with their cognate SNARE partners on the target membrane to trigger exocytosis. In myelin, vesicles have been observed in the inner tongue and are thought to travel through "myelinic channels" extending through compact myelin regions 5,6,[18][19][20] , but the molecular components and function of these vesicles are unclear. Previous studies reported the upregulation of v-SNARE isoforms VAMP3 and VAMP7 in myelinating oligodendrocytes 21,22 .…”

“…Each myelin sheath is a continuous extension of the oligodendrocyte plasma membrane, and a single oligodendrocyte has been estimated to increase its membrane area by several thousand-fold 4 , requiring extensive addition of new membrane. Myelin sheaths are thought to grow in thickness and length by extending their innermost layer, or inner tongue, around and along the axon 5,6 , but the cellular machinery that adds new membrane to power myelination is unknown. Beyond developmental myelination, experience and learning during adulthood can induce oligodendrocytes to form new myelin or restructure existing myelin sheaths, adapting myelination patterns to altered neural circuitry and potentially accelerating regeneration after demyelination [7][8][9][10][11][12][13] .…”

Myelin insulation as a risk factor for axonal degeneration in autoimmune demyelinating disease

“…Unpaired two-tailed Welch's t test. c, Clinical EAE scoring(1)(2)(3)(4)(5)(6)(7)(8)(9)(10) shows an ameliorated disease course in hMbp mice compared to wildtype controls. n Ctrl EAE = 13, n hMbp EAE = 10.…”

“…Despite this, and based on the assumption that de-and amyelinated axons are especially vulnerable to injury, initial damage in MS is proposed to occur at areas naturally devoid of myelin, such as nodes of Ranvier [4][5][6] . We and others hypothesized that oligodendrocytes provide trophic support to axons [7][8][9] because axons are isolated from extracellular glucose at least in part by myelin itself 10 . Consequently, fully myelinated axons should be most dependent on oligodendrocytemediated metabolic support, which, in turn, would make myelinated axons most vulnerable to autoimmune attacks that impact the oligodendrocyte's capacity to support the myelinated axon.…”