Syk kinases are required for spinal commissural axon repulsion at the midline via the ephrin/Eph pathway.
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.
INSERM U1217, Institut NeuroMyoGène, Lyon F-69000, France CNRS UMR5310, Institut NeuroMyoGène, Lyon F-69000, France University Claude Bernard Lyon 1, Lyon F-69000, France nelly.noraz@inserm.fr.
Nelly
0000-0003-4076-9773
N
Noraz
INSERM U1217, Institut NeuroMyoGène, Lyon F-69000, France CNRS UMR5310, Institut NeuroMyoGène, Lyon F-69000, France University Claude Bernard Lyon 1, Lyon F-69000, France.
Iness
I
Jaaoini
INSERM U1217, Institut NeuroMyoGène, Lyon F-69000, France CNRS UMR5310, Institut NeuroMyoGène, Lyon F-69000, France University Claude Bernard Lyon 1, Lyon F-69000, France.
Camille
C
Charoy
INSERM U1217, Institut NeuroMyoGène, Lyon F-69000, France CNRS UMR5310, Institut NeuroMyoGène, Lyon F-69000, France University Claude Bernard Lyon 1, Lyon F-69000, France.
Chantal
C
Watrin
INSERM U1217, Institut NeuroMyoGène, Lyon F-69000, France CNRS UMR5310, Institut NeuroMyoGène, Lyon F-69000, France University Claude Bernard Lyon 1, Lyon F-69000, France.
Naura
N
Chounlamountri
INSERM U1217, Institut NeuroMyoGène, Lyon F-69000, France CNRS UMR5310, Institut NeuroMyoGène, Lyon F-69000, France University Claude Bernard Lyon 1, Lyon F-69000, France.
Aurélien
A
Benon
INSERM U1217, Institut NeuroMyoGène, Lyon F-69000, France CNRS UMR5310, Institut NeuroMyoGène, Lyon F-69000, France University Claude Bernard Lyon 1, Lyon F-69000, France.
Céline
C
Malleval
INSERM U1064, Institut de Transplantation Urologie-Néphrologie, Nantes F-44035, France.
Hélène
H
Boudin
INSERM U1217, Institut NeuroMyoGène, Lyon F-69000, France CNRS UMR5310, Institut NeuroMyoGène, Lyon F-69000, France University Claude Bernard Lyon 1, Lyon F-69000, France Hospices Civils de Lyon, Lyon F-69000, France.
Jérôme
J
Honnorat
INSERM U1217, Institut NeuroMyoGène, Lyon F-69000, France CNRS UMR5310, Institut NeuroMyoGène, Lyon F-69000, France University Claude Bernard Lyon 1, Lyon F-69000, France.
Valérie
V
Castellani
INSERM U1217, Institut NeuroMyoGène, Lyon F-69000, France CNRS UMR5310, Institut NeuroMyoGène, Lyon F-69000, France University Claude Bernard Lyon 1, Lyon F-69000, France.
Véronique
V
Pellier-Monnin
D000818:Animals; D001369:Axons / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000378:metabolism; D004705:Endocytosis; D036389:Ephrin-B3 / Q000378:metabolism*; D020439:Growth Cones / Q000378:metabolism; D018345:Mice, Knockout; D010766:Phosphorylation; D036183:Receptor, EphB2 / Q000378:metabolism*; D015398:Signal Transduction; D013116:Spinal Cord / Q000378:metabolism*; D000072377:Syk Kinase / Q000378:metabolism*
D036389:Ephrin-B3; C586311:Ephb2 protein, mouse; D036183:Receptor, EphB2; D000072377:Syk Kinase
Commissural axons; Ephrin/Eph; Neural tube; Repulsion; Syk kinases