The function of contactin‐2/TAG‐1 in oligodendrocytes in health and demyelinating pathology

Abstract

The oligodendrocyte maturation process and the transition from the pre-myelinating to the myelinating state are extremely important during development and in pathology. In the present study, we have investigated the role of the cell adhesion molecule CNTN2/TAG-1 on oligodendrocyte proliferation, differentiation, myelination, and function during development and under pathological conditions. With the combination of in vivo, in vitro, ultrastructural, and electrophysiological methods, we have mapped the expression of CNTN2 protein in the oligodendrocyte lineage during the different stages of myelination and its involvement on oligodendrocyte maturation, branching, myelin-gene expression, myelination, and axonal function. The cuprizone model of central nervous system demyelination was further used to assess CNTN2 in pathology. During development, CNTN2 can transiently affect the expression levels of myelin and myelin-regulating genes, while its absence results in reduced oligodendrocyte branching, hypomyelination of fiber tracts and impaired axonal conduction. In pathology, CNTN2 absence does not affect the extent of de- and remyelination. However during remyelination, a novel, CNTN2-independent mechanism is revealed that is able to recluster voltage gated potassium channels (VGKCs) resulting in the improvement of fiber conduction.

Molecular and Cellular Substrates for the Friedreich Ataxia. Significance of Contactin Expression and of Antioxidant Administration

“…However, stronger effects were demonstrated in the case of neural adhesive glycoproteins provided with key relevant regulatory roles in neural developmental control as is typically the case for Contactin family components [ 77 ] and in particular for Contactin 1 [ 55 , 78 ], for which a stronger downregulation, accounting to about 50% was demonstrated in the dorsal horn. This Contactin 1 behavior could be explained based on its cell type-specificity, which, besides the neuronal lineage, also concerns the glial, in particular the oligodendrocyte lineage in which it participates to the mechanism of myelination through its effects on nodal/paranodal regions organization [ 55 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 ].…”

Ablation of CNTN2+ Pyramidal Neurons During Development Results in Defects in Neocortical Size and Axonal Tract Formation

“…In the adult rodent nervous system, there is knowledge of TAG-1 expression in the cerebellum, the mitral cells of the olfactory bulb, the hippocampus, and the juxtaparanodal domains of myelinated fibers (both at the axonal and glial membranes; Yoshihara et al, 1995; Wolfer et al, 1998; Traka et al, 2002). Considering the wider extent of detection of Tag-1 EGFP during the stages analyzed compared to the immunodetection with current antibodies, the transgenic strain in question is a valuable tool to further study the protein in the adult mouse (Bastakis et al, 2015; Zoupi et al, 2018). This could allow a variety of studies focusing on neurons, glia and potentially interneurons, as already seen in recent publications.…”

Rescuing the negative impact of human endogenous retrovirus envelope protein on oligodendroglial differentiation and myelination

“…Further studies on modulated V‐ATPase activity and TLR4 signaling in the context of de‐ and remyelination in vivo will be important to conduct and therefore deserve increased attention. Of note, a couple of recent studies identified other promising signaling pathways promoting (re)myelination in rodent models such as activated by teriflunomide (Göttle et al, ), the histamine receptor 3 modulator GSK247246 (Chen et al, ), the dual inhibitor VP3.15 (Medina‐Rodriguez et al, ), muscarinic receptor antagonists (Welliver et al, ) and contactin‐2/TAG‐1 (Zoupi et al, ). Although, these are attractive targets they have not yet advanced in terms of clinical assessment and application.…”