Cytoskeletal Linker Protein Dystonin Is Not Critical to Terminal Oligodendrocyte Differentiation or CNS Myelination

Abstract

Oligodendrocyte differentiation and central nervous system myelination require massive reorganization of the oligodendrocyte cytoskeleton. Loss of specific actin- and tubulin-organizing factors can lead to impaired morphological and/or molecular differentiation of oligodendrocytes, resulting in a subsequent loss of myelination. Dystonin is a cytoskeletal linker protein with both actin- and tubulin-binding domains. Loss of function of this protein results in a sensory neuropathy called Hereditary Sensory Autonomic Neuropathy VI in humans and dystonia musculorum in mice. This disease presents with severe ataxia, dystonic muscle and is ultimately fatal early in life. While loss of the neuronal isoforms of dystonin primarily leads to sensory neuron degeneration, it has also been shown that peripheral myelination is compromised due to intrinsic Schwann cell differentiation abnormalities. The role of this cytoskeletal linker in oligodendrocytes, however, remains unclear. We sought to determine the effects of the loss of neuronal dystonin on oligodendrocyte differentiation and central myelination. To address this, primary oligodendrocytes were isolated from a severe model of dystonia musculorum, Dstdt-27J, and assessed for morphological and molecular differentiation capacity. No defects could be discerned in the differentiation of Dstdt-27J oligodendrocytes relative to oligodendrocytes from wild-type littermates. Survival was also compared between Dstdt-27J and wild-type oligodendrocytes, revealing no significant difference. Using a recently developed migration assay, we further analysed the ability of primary oligodendrocyte progenitor cell motility, and found that Dstdt-27J oligodendrocyte progenitor cells were able to migrate normally. Finally, in vivo analysis of oligodendrocyte myelination was done in phenotype-stage optic nerve, cerebral cortex and spinal cord. The density of myelinated axons and g-ratios of Dstdt-27J optic nerves was normal, as was myelin basic protein expression in both cerebral cortex and spinal cord. Together these data suggest that, unlike Schwann cells, oligodendrocytes do not have an intrinsic requirement for neuronal dystonin for differentiation and myelination.

N-Wasp Regulates Oligodendrocyte Myelination

“…It is interesting to note that, in terms of actin dynamics, the process of axonal sorting by Schwann cells could actually be considered equivalent to oligodendrocytes branching and their initial ensheathment of axons (Feltri et al, 2016). Hence, supported by studies of several other regulators of actin dynamics, such as Myosin II (Wang et al, 2008), Dynamin 2 (Gerber et al, 2019), and Dystonin I (Kornfeld et al, 2016), our findings indicate the existence of fundamental differences in the role actin reorganization plays during CNS and PNS myelination. Alternatively, the relative limited effect N-Wasp ablation has on CNS compared with PNS myelination could result from a possible compensatory mechanism by other actin nucleation-promoting factors of the Arp2/3 complex.…”

Prediction of MicroRNA and Gene Target in Synovium-Associated Pain of Knee Osteoarthritis Based on Canonical Correlation Analysis

“…Dystonin is a cytoskeletal crosslinker protein that binds to actin and tubulin. This protein dysfunction can lead to sensory neuropathy, known as the human muscle-atrophic sensory autonomic neuropathy [28]. According to our research, this is the first time that dystonin and synovium pain in KOA have correlated.…”

Characterization of gastrointestinal pathologies in the dystonia musculorum mouse model for hereditary sensory and autonomic neuropathy type VI

“…We also assessed whether It is likely that the ENS contains other compensatory spectraplakin proteins (eg, Macf1) that make up for dystonin loss-of-function, which has been suggested for other cell types that express dystonin but do not exhibit defects or cell death. 5,[42][43][44] Nevertheless, Dst dt-27J mice do exhibit a small reduction in GI motility as well as a thinning of the mucous layer lining the colon. We believe that these effects are linked to dystonin loss-of-function impacting the extrinsic neural input on the ENS.…”

“…Our recent findings related to Dst ‐ a3 upregulation and compensation in dystonin‐dependent tissues would also suggest that the lack of any increase in Dst‐a/b3 expression at any GIT level in Dst dt‐Tg4 mice might indicate that the enteric nervous system is not impacted by dystonin loss‐of‐function (Figure S3). It is likely that the ENS contains other compensatory spectraplakin proteins (eg, Macf1) that make up for dystonin loss‐of‐function, which has been suggested for other cell types that express dystonin but do not exhibit defects or cell death …”