The Syk kinases orchestrate cerebellar granule cell tangential migration

Abstract

The tyrosine kinases of the Syk family are essential components of the well-characterized immunoreceptor ITAM-based signaling pathway. However, ITAM-based signaling typically does not function in isolation. Instead, it is enmeshed in the molecular network controlling cellular adhesion and chemotaxis. Consistent with the increasing number of data involving ITAM-bearing molecules in neuronal functions, we previously depicted a role for Syk kinases in the establishment of neuronal connectivity. In the developing cerebellum, we found that Syk is essentially expressed in the granule cells (GC) and more importantly, phosphorylated on tyrosine residues representative of an active form of the kinase in tangentially migrating GC. In light of these findings, experiments were performed to establish the implication of Syk in this process. We showed that Syk state of phosphorylation is spatiotemporally regulated during GC ontogeny. Moreover, the analysis of external granular layer microexplants treated with a Syk pharmacological inhibitor together with the quantification of ectopic GC in Syk+/−; ZAP-70−/− mutant mice brought evidence of a requirement of Syk in GC tangential migration. Syk phosphorylation was induced by EphB2 engagement and locally turned down by a not yet identified factor that could in part explain the restricted pattern of Syk phosphorylation observed along GC migratory route. Whereas Syk kinase activity appeared not essential for ephrin/Eph-mediated axon extension, it might provide polarization signals required for proper nucleus translocation during GC migration. In conclusion, Syk kinase acts downstream of receptors controlling GC tangential migration.