Functional interplay between ganglioside GM1 and cross‐linking galectin‐1 induces axon‐like neuritogenesis via integrin‐based signaling and TRPC5‐dependent Ca²⁺ influx

Abstract

Axon-like neuritogenesis in neuroblastoma (NG108-15) cells and primary cerebellar granular neurons is furthered by the presence of ganglioside GM1. We describe here that galectin-1 (Gal-1), a homobivalent endogenous lectin, is an effector by cross-linking the ganglioside and its associated glycoprotein α5β1-integrin. The thereby triggered signaling cascade involves autophosphorylation of focal adhesion kinase and activation of phospholipase Cγ and phosphoinositide-3 kinase. This leads to a transient increase in the intracellular Ca2+ concentration by opening of TRPC5 channels, which belong to the signal transduction-gated cation channels. Controls with GM1-defective cells (NG-CR72, and neurons from ganglio-series KO mice) were retarded in axonal growth, underscoring the relevance of GM1 as functional counterreceptor for Gal-1. The lectin’s presence was detected in the NG108-15 cells, suggesting an autocrine mechanism of action, and in astrocytes in situ. Gal-1, as cross-linking lectin, can thus translate metabolic conversion of ganglioside GD1a to GM1 by neuraminidase action into axon growth.

Keeping it trim: roles of neuraminidases in CNS function

“…Clustering of GM1 with laminin-1, along with laminin-1 self-assembly, also promotes relocation and enrichment of β1-integrin in lipid rafts and enhances combined laminin-integrin signaling to trigger neurite outgrowth [ 87 ]. Galectin-1 (Gal-1) was recently reported to cross-link GM1 ganglioside and α5 β1-integrin [ 88 ]. In normal cerebellar granule neurons and neuroblastoma NG108–15 cells, this led to a transient increase in intracellular Ca 2+ by opening TRPC5 channels whereas cells from mice lacking major gangliosides, including GM1, showed retarded axonogenesis, underscoring the importance of GM1 for this process [ 88 ].…”

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

“…In particular, the reported expression of members of the galectin family, tissue lectins with β-galactoside binding capacity 18 , 19 , has stimulated the research of their functional implications in nervous system physiology. So far, galectin-1 (Gal-1) 20 – 24 , galectin-3 (Gal-3) 25 , 26 , and galectin-4 (Gal-4) 27 , 28 , have been related to axon growth and guidance, differentiation of microglia and oligodendrocytes, or nerve regeneration. LacNAc-dependent sorting of contactin suggested the participation of galectin interactions in myelin organization, according to our previous report of a directional Gal-4-based axon transport of LacNAc-bearing glycoproteins.…”

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

“…Hereby, the residence time of counterreceptors on the surface is intimately regulated, in critical dependence of the presence of cognate glycans. Underscoring the physiological potential of galectins, their presence is under strict control, and first cases have been described for an intimate spatiotemporal co-regulation of galectin/counterreceptor presentation, for example, the Gal-1/ganglioside GM1 route of communication between effector/regulatory T cells and in axon growth induction [79,80]. This survey explains why it is likely that galectins will also be important in CNS processes.…”