An Integrin–Contactin Complex Regulates CNS Myelination by Differential Fyn Phosphorylation

Abstract

The understanding of how adhesion molecules mediate the axon-glial interactions in the CNS that ensure target-dependent survival of oligodendrocytes and initiate myelination remains incomplete. Here, we investigate how signals from adhesion molecules can be integrated to regulate these initial steps of myelination. We first demonstrate that the Ig superfamily molecule contactin is associated in oligodendrocytes with integrins, extracellular matrix receptors that regulate target-dependent survival by amplification of growth factor signaling. This amplification is inhibited by small interfering RNA-mediated knockdown of contactin in oligodendrocytes. In contrast, the presence of L1-Fc, the extracellular portion of a contactin ligand expressed on axons, enhanced survival and additionally promoted myelination in cocultures of neurons and oligodendrocytes. We further demonstrate that the signals from contactin and integrin are integrated by differential phosphorylation of the Src family kinase Fyn. Integrin induced dephosphorylation of the inhibitory Tyr-531, whereas contactin increased phosphorylation of both Tyr-531 and the activating Tyr-420. The combined effect is an enhanced activity of Fyn and also a dynamic regulation of the phosphorylation/dephosphorylation balance of Fyn, as required for normal cell adhesion and spreading. We conclude, therefore, that a novel integrin/contactin complex coordinates signals from extracellular matrix and the axonal surface to regulate both oligodendrocyte survival and myelination by controlling Fyn activity.

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

“…Earlier studies of central myelinated nerves described Contactin's distribution at nodes of Ranvier and paranodes (11,16). Contactin is also strongly expressed by developing oligodendrocytes in culture (17)(18)(19), but its distribution on oligodendrocytes in myelinated nerves has remained obscure. We therefore asked whether oligodendrocytes in vivo express Contactin.…”

“…In vitro experiments have implicated Contactin-mediated signals in triggering events that lead to myelin membrane expansion (18,19). To address if loss of Contactin affected the extension of oligodendrocyte membranes, we generated Cntn1-KO and WT littermate mice expressing GFP in the oligodendrocyte lineage.…”

“…In central myelin, Contactin delineates both nodes of Ranvier and paranodes (11,16). Cultured oligodendrocytes also express Contactin, which up-regulates myelin-basic protein (MBP) mRNA translation and differentiation when stimulated with recombinant L1-ligand protein (17)(18)(19). The functions of Contactin in central myelination, and in particular possible contributions of Contactin expressed by oligodendrocytes, have not been reported.…”

Discovery and initial verification of differentially abundant proteins between multiple sclerosis patients and controls using iTRAQ and SID-SRM

“…However, the two peptides used to monitor the abundance of contactin-1 did not show consistent significance between and within the different groups (Supplementary Table 6). Contactin-1 is a cell-adhesion glycoprotein distributed in the brain [49], and is highly involved in the regulation of oligodendrocyte survival, maturation, and myelination [50,51]. In the literature, increased abundance of contactin-1 have been verified in SPMS compared to controls using multiplex immunoassays [24], and decreased levels have also been found in multiple sclerosis compared to OND [30].…”

Promoting remyelination for the treatment of multiple sclerosis: opportunities and challenges

“…L1CAM has also been reported to be involved in the initiation of myelin formation [62,63] . it is downregulated on myelinated axons and re-expressed in regenerating axons after spinal cord injury [64,65] .…”