Role of a Contactin multi‐molecular complex secreted by oligodendrocytes in nodal protein clustering in the CNS

Abstract

The fast and reliable propagation of action potentials along myelinated fibers relies on the clustering of voltage‐gated sodium channels at nodes of Ranvier. Axo‐glial communication is required for assembly of nodal proteins in the central nervous system, yet the underlying mechanisms remain poorly understood. Oligodendrocytes are known to support node of Ranvier assembly through paranodal junction formation. In addition, the formation of early nodal protein clusters (or prenodes) along axons prior to myelination has been reported, and can be induced by oligodendrocyte conditioned medium (OCM). Our recent work on cultured hippocampal neurons showed that OCM‐induced prenodes are associated with an increased conduction velocity (Freeman et al., 2015). We here unravel the nature of the oligodendroglial secreted factors. Mass spectrometry analysis of OCM identified several candidate proteins (i.e., Contactin‐1, ChL1, NrCAM, Noelin2, RPTP/Phosphacan, and Tenascin‐R). We show that Contactin‐1 combined with RPTP/Phosphacan or Tenascin‐R induces clusters of nodal proteins along hippocampal GABAergic axons. Furthermore, Contactin‐1‐immunodepleted OCM or OCM from Cntn1‐null mice display significantly reduced clustering activity, that is restored by addition of soluble Contactin‐1. Altogether, our results identify Contactin‐1 secreted by oligodendrocytes as a novel factor that may influence early steps of nodal sodium channel cluster formation along specific axon populations.

An alternative mechanism of early nodal clustering and myelination onset in GABAergic neurons of the central nervous system

“…The occurrence of evenly spaced clusters of nodal components along axons prior to myelination, initially reported on retinal ganglion cells (Kaplan et al, 2001(Kaplan et al, , 1997 was also observed in vitro and in vivo on GABAergic hippocampal neurons, but not on pyramidal hippocampal neurons (Bonetto et al, 2019;Dubessy et al, 2019;Freeman et al, 2015). These early clusters, which share features with nodes of Ranvier (identical subunits β1Nav and β2Nav have been shown to play critical roles in modulating the membrane density and the function of αNav (Chen et al, 2002;Kazen-Gillespie et al, 2000;O'Malley and Isom, 2015;Patton et al, 1994).…”

“…Whether they might be linked to neuronal electrical activity or to locally secreted factors is still to be characterized. The fact that early nodelike clustering also depends on oligodendroglial secreted cues (Dubessy et al, 2019;Freeman et al, 2015;Kaplan et al, 2001Kaplan et al, , 1997 further shows that a tightly regulated dual interaction between neuron and glia is required for myelinated fiber organization.…”

“…Furthermore, recently generated data suggest that Nfasc186 could be partially recruited to forming clusters by relocation from the membrane pool (data not shown). It is possible that extracellular partners, some of them being secreted by oligodendrocytes, interact with nodal CAMs in this second step, as it has been shown that oligodendrocyte secreted factor(s) are required for node-like clusters assembly (Dubessy et al, 2019;Freeman et al, 2015;Kaplan et al, 2001Kaplan et al, , 1997Susuki et al, 2013).…”

“…The mechanisms underlying the initiation of nodal clustering are well described in the peripheral nervous system (PNS) and rely on the tripartite interaction between axonal Nfasc186 and glial Gliomedin and NrCAM (Eshed et al, 2007(Eshed et al, , 2005Feinberg et al, 2010;Zhang et al, 2012). The assembly mechanisms governing nodes of Ranvier clustering in the central nervous system (CNS) appear, however, to be more complex and involve an interplay of several overlapping and redundant mechanisms, ultimately converging on the fact that neuron-oligodendroglia interactions are necessary for CNS nodal assembly (Amor et al, 2017;Brivio et al, 2017;Dubessy et al, 2019;Freeman et al, 2015;Susuki et al, 2013).…”

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 ].…”