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 Syk(-/-); Zap70(-/-) mouse 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.
Highlights
The function of the non-receptor spleen tyrosine kinase (Syk) family members Syk and Zap70 has been well characterized in cells of the hematopoietic lineage
Syk kinases appeared phosphorylated in precrossing axons extending from the cell bodies residing in the dorsal regions of the spinal cord, in crossing axons at the floor plate forming the ventral commissure, and in postcrossing axons coursing in the ventral as well as the lateral funiculi (Fig. 1A,B)
Syk activity and growth cone responsiveness to guidance cues We have shown in this study that Syk kinases are required for ephrin B3-mediated commissural neuron growth cone collapse, and we collected data implicating EphB2 in this process
Summary
The function of the non-receptor spleen tyrosine kinase (Syk) family members Syk and Zap ( known as ZAP-70) has been well characterized in cells of the hematopoietic lineage They relay signals emanating from classical immunoreceptors such as TCR, BCR, NKR and FcR, thereby controlling their homeostasis and functional outcome. Upon ligand recognition and receptor clustering, tyrosines within the ITAM are dually phosphorylated by Src family kinases, providing a docking site for the tandem SH2 domains of the Syk family kinases. These early events allow the recruitment and activation of both kinase families and serve as a crucial link to adapter molecules [e.g. Lat and SLP-76 (Lcp2)] capable of organizing multiple signaling pathways in a spatiotemporal manner. Downstream signaling ensues principally via the Ras, DAG and calcium-dependent signaling pathways, as well as via actin dynamics regulatory molecules (Smith-Garvin et al, 2009)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
