Contactin-1 regulates myelination and nodal/paranodal domain organization in the central nervous system

Abstract

Myelin, a multilayered membrane sheath formed by oligodendrocytes around axons in the CNS, enables rapid nerve impulse conduction and sustains neuronal health. The signals exchanged between axons and oligodendrocytes in myelin remain to be fully elucidated. Here we provide genetic evidence for multiple and critical functions of Contactin-1 in central myelin. We document dynamic Contactin-1 expression on oligodendrocytes in vivo, and progressive accumulation at nodes of Ranvier and paranodes during postnatal mouse development. Nodal and paranodal expression stabilized in mature myelin, but overall membranous expression diminished. Contactin-1-deficiency disrupted paranodal junction formation as evidenced by loss of Caspr, mislocalized potassium K v 1.2 channels, and abnormal myelin terminal loops. Reduced numbers and impaired maturation of sodium channel clusters accompanied this phenotype. Histological, electron microscopic, and biochemical analyses uncovered significant hypomyelination in Contactin-1-deficient central nerves, with up to 60% myelin loss. Oligodendrocytes were present in normal numbers, albeit a minor population of neuronal/glial antigen 2-positive (NG2 + ) progenitors lagged in maturation by postnatal day 18, when the mouse null mutation was lethal. Major contributing factors to hypomyelination were defects in the generation and organization of myelin membranes, as judged by electron microscopy and quantitative analysis of oligodendrocyte processes labeled by GFP transgenically expressed from the proteolipid protein promoter. These data reveal that Contactin-1 regulates both myelin formation and organization of nodal and paranodal domains in the CNS. These multiple roles distinguish central Contactin-1 functions from its specific role at paranodes in the periphery, and emphasize mechanistic differences in central and peripheral myelination.

Two novel variants in CNTNAP1 in two siblings presenting with congenital hypotonia and hypomyelinating neuropathy

“…15 Finally, dissociations of the myelin loops from the axons were described in optic nerves of Cntn1-KO mice. 16 Given that similar lesions were observed in our patients in sural nerve biopsy, such unusual anomalies could be a hallmark of Caspr/Contactin-1 complex loss of function.…”

Structural Characterization of the Extracellular Domain of CASPR2 and Insights into Its Association with the Novel Ligand Contactin1

“…CNTN1 has also been implicated in hippocampal neurogenesis and cell proliferation as well as in synaptic plasticity and memory in the adult mouse (12). Expression of CNTN1 in both neurons and oligodendrocytes suggests a role in myelination, which has been confirmed by low levels of myelin basic protein in the CNTN1 KO mouse and by its interaction with other molecules involved in myelination (13)(14)(15)(16).…”

The role of Gpi-anchored axonal glycoproteins in neural development and neurological disorders

“…in a trans interaction. However, oligodendrocytes themselves express CNTN1 (Haenisch et al, 2005;Çolakoğlu et al, 2014) making it possible that cis interactions are involved, which may affect how Notch is trafficked; the trafficking pathways taken by Notch during signalling affects both the level and type of signal generated (Yap & Winckler, 2015). This is pertinent to the TAG/F3 experiments in the cortex since ectopic expression of CNTN1 is induced in cells that may already express both CNTN1 and CNTN2 (it is not clear whether this is in the same or different cells), which suggests that it may be the levels, or the subcellular localisations of these proteins that is critical to the signalling outcome.…”