From axon-glial signalling to myelination: the integrating role of oligodendroglial Fyn kinase

Abstract

Central nervous system myelination requires recognition and signalling processes between neuronal axons and oligodendrocytes. Complex cellular rearrangements occur in myelination-competent oligodendrocytes requiring spatio-temporal control mechanisms. Although the molecular repertoire is becoming increasingly transparent, the signalling mechanisms governing myelination initiation are only poorly understood. The non-receptor tyrosine kinase Fyn has been implicated in axon-glial signal transduction and in several cellular processes required for oligodendrocyte maturation and myelination. Here, we review oligodendroglial Fyn signalling and discuss the role of Fyn in axon-glia interaction mediating myelination.

Fig. 1

Domain organization of Fyn kinase. Top Fyn kinase contains an N-terminal SH4 domain anchoring the protein in the plasma membrane by myristoylation (Myr), the SH3 and SH2 protein interaction domains, an SH1 or kinase domain and a C-terminus with the conserved regulatory tyrosine residue 531 (Y531). Bottom In the inactive or basal state the kinase is in a closed conformation due to intramolecular binding of the SH2 domain with the phosphorylated Y531 and the SH3 domain with a linker region between SH2 and SH1/kinase domain. Upon dephosphorylation of the C-terminal tyrosine or binding of external ligands to SH2 or SH3 domains, the conformation changes to an open form that is regarded as the active state. Intermolecular autophosphorylation of tyrosine 420 stabilises the active state of the kinase. Note that palmitoylation in the SH4 domain can direct Fyn into lipid raft microdomains

Fig. 2

The role of Fyn as central integrator and mediator of axon–glia signalling. Axon-derived signals are sensed by oligodendroglial membrane receptors that modulate Fyn kinase activity. Fyn mediates downstream signalling that can be divided into three major pathways: (1) the RhoA/Cdc42/Rac1-dependent pathway modulates actin dynamics and mediates cell survival and morphological differentiation; (2) recruitment of the microtubule cytoskeleton contributes to cell polarisation and may facilitate axon-directed cargo transport; and (3) activated Fyn controls localised myelin protein synthesis by affecting mRNA transport, stability, and translational regulation. In summary, these pathways integrate axonal signals to spatiotemporally regulate myelin formation. See text for details