Syk kinases are required for spinal commissural axon repulsion at the midline via ephrin/Eph pathway

Abstract

In the hematopoietic system, Syk family tyrosine kinases are essential components of immunoreceptor ITAM-based signaling. While there is increasing data indicating the involvement of immunoreceptors in neural functions, the contribution of Syk kinases remains obscure. Previously, we identified phosphorylated forms of Syk kinases in specialized populations of migrating neurons or projecting axons. Moreover, we identified ephrin/Eph as guidance molecules utilizing the ITAM-bearing CD3zeta (Cd247) and associated Syk kinases for the growth cone collapse response induced in vitro. Here, we show that in the developing spinal cord, Syk is phosphorylated in navigating commissural axons. By analyzing axon trajectories in open-book preparations of Sykmouse embryos, we show that Syk kinases are dispensable for attraction towards the midline but confer growth cone responsiveness to repulsive signals that expel commissural axons from the midline. Known to serve a repulsive function at the midline, ephrin B3/EphB2 are obvious candidates for driving the Syk-dependent repulsive response. Indeed, Syk kinases were found to be required for ephrin B3-induced growth cone collapse in cultured commissural neurons. In fragments of commissural neuron-enriched tissues, Syk is in a constitutively phosphorylated state and ephrin B3 decreased its level of phosphorylation. Direct pharmacological inhibition of Syk kinase activity was sufficient to induce growth cone collapse. In conclusion, Syk kinases act as a molecular switch of growth cone adhesive and repulsive responses.

TAGAP instructs Th17 differentiation by bridging Dectin activation to EPHB2 signaling in innate antifungal response

“…4a). EPHB2 was previously found to bind to Syk in the cells 26 , and this interaction was confirmed by co-immunoprecipitation ( Fig. 4b).…”

SYK Inhibition Potentiates the Effect of Chemotherapeutic Drugs on Neuroblastoma Cells In Vitro

“…Among its various functions, SYK promotes, in concert with PKCδ, the expression of anti-apoptotic Mcl-1 in B-cell chronic lymphocytic leukemia (CLL) [10] and regulates actin filament assembly and dynamics through phosphorylation of cortactin and cofilin in ovarian cancer, thereby promoting migration and invasion [11]. Furthermore, phosphorylated SYK has been observed in specific cell types and areas of the developing nervous system and diverse functions have been described [12,13,14].…”

A Subtle Network Mediating Axon Guidance: Intrinsic Dynamic Structure of Growth Cone, Attractive and Repulsive Molecular Cues, and the Intermediate Role of Signaling Pathways

“…These guidance cues might act in different spatial and temporal windows. Thus, proper coordination between attraction and repulsion responses of a complex array of guidance cues plays a crucial role in developing commissural axons [164].…”