Neurons define non-myelinated axon segments by the regulation of galectin-4-containing axon membrane domains

Abstract

The mechanism underlying selective myelination of axons versus dendrites or neuronal somata relies on the expression of somatodendritic membrane myelination inhibitors (i.e. JAM2). However, axons still present long unmyelinated segments proposed to contribute to axonal plasticity and higher order brain functions. Why these segments remain unmyelinated is still an unresolved issue. The bifunctional lectin galectin-4 (Gal-4) organizes the transport of axon glycoproteins by binding to N-acetyllactosamine (LacNac) termini of N-glycans. We have shown that Gal-4 is sorted to segmental domains (G4Ds) along the axon surface, reminiscent of these long unmyelinated axon segments in cortical neurons. We report here that oligodendrocytes (OLGs) do not deposit myelin on Gal-4 covered surfaces or myelinate axonal G4Ds. In addition, Gal-4 interacts and co-localizes in G4Ds with contactin-1, a marker of another type of non-myelinated segments, the nodes of Ranvier. Neither Gal-4 expression nor G4D dimensions are affected by myelin extracts or myelinating OLGs, but are reduced with neuron maturation. As in vitro, Gal-4 is consistently segregated from myelinated structures in the brain. Our data shape the novel concept that neurons establish axon membrane domains expressing Gal-4, the first inhibitor of myelination identified in axons, whose regulated boundaries delineate myelination-incompetent axon segments along development.

The oligodendrocyte growth cone and its actin cytoskeleton: A fundamental element for progenitor cell migration and CNS myelination

“…Indeed, neuronal junction adhesion molecule 2 (JAM2) has been identified as a nonpermissive somatodendritic cue necessary for preventing non‐axonal myelination of neurons (Redmond et al, ). Similarly, galectin‐4 has been recently proposed to function as a repulsive cue for the initiation of myelination and to thereby define nonmyelinated axonal segments (Diez‐Revuelta et al, ). Members of the IgLON family, which represent GPI anchored adhesion molecules expressed by both OLGs and neurons, have also been identified as repulsive cues with functional importance in preventing precocious developmental myelination of specific fiber tracts (Sharma et al, ).…”

Detection of malignancy‐associated phosphoproteome changes in human colorectal cancer induced by cell surface binding of growth‐inhibitory galectin‐4

“…Structurally, gal-4 is bivalent. It is constituted by two different lectin domains connected by a linker (42 amino acids for human gal-4) so that it is an ideal crosslinker of glycans in cell (trans) bridging and surface (cis) lattice formation (15)(16)(17)(18)(19).…”

The emerging role of galectins in (re)myelination and its potential for developing new approaches to treat multiple sclerosis

“…Sorts and organizes transport of axonal L1 in a sulfatide-dependent manner [125] Gal-4 deposits on axons inhibit myelination Possible role in recruitment of contactin-1 and correct targeting of nodes of Ranvier [134] topography of olfactory axons in Lgal1 −/− mice [117,[119][120][121]. Galectins-3 and -4 are transiently expressed during development and downregulated at the onset of myelination [122][123][124].…”

“…When appropriately clustered, L1 binds to oligodendroglial contactin (also called F3) and activates Fyn kinase, which initiates MBP-specific mRNA synthesis and myelin biogenesis in oligodendrocytes [130][131][132][133]. In addition, axons harbor discrete galectin-4-containing domains that impede the deposition of myelin by oligodendrocytes [134]. In these myelination-excluding domains, galectin-4 interacts with axonal contactin-1, which in myelinated axons is present in the non-myelinated nodes of Ranvier [134].…”