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The Journal of Neuroscience, April 29, 2009, 29(17):5690-5700; doi:10.1523/JNEUROSCI.0265-09.2009

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Development/Plasticity/Repair
Src Family Kinases Are Required for Limb Trajectory Selection by Spinal Motor Axons

Tzu-Jen Kao,¹ Elena Palmesino,¹ and Artur Kania^1,2,3

¹Institut de recherches cliniques de Montréal, Montréal, Quebec H2W 1R7, Canada, ²Department of Anatomy and Cell Biology, Division of Experimental Medicine, McGill University, Montréal, Quebec H3A 2B2, Canada, and ³Faculté de médecine, Université de Montréal, Montréal, Quebec H3C 3J7, Canada

Correspondence should be addressed to Artur Kania, Institut de recherches cliniques de Montréal, 110, avenue des Pins Ouest, Montréal, QC H2W 1R7, Canada. Email: artur.kania{at}ircm.qc.ca

Signal relay by guidance receptors at the axonal growth cone is a process essential for the assembly of a functional nervous system. We investigated the in vivo function of Src family kinases (SFKs) as growth cone guidance signaling intermediates in the context of spinal lateral motor column (LMC) motor axon projection toward the ventral or dorsal limb mesenchyme. Using in situ mRNA detection we determined that Src and Fyn are expressed in LMC motor neurons of chick and mouse embryos at the time of limb trajectory selection. Inhibition of SFK activity by C-terminal Src kinase (Csk) overexpression in chick LMC axons using in ovo electroporation resulted in LMC axons selecting the inappropriate dorsoventral trajectory within the limb mesenchyme, with medial LMC axon projecting into the dorsal and ventral limb nerve with apparently random incidence. We also detected LMC axon trajectory choice errors in Src mutant mice demonstrating a nonredundant role for Src in motor axon guidance in agreement with gain and loss of Src function in chick LMC neurons which led to the redirection of LMC axons. Finally, Csk-mediated SFK inhibition attenuated the retargeting of LMC axons caused by EphA or EphB over-expression, implying the participation of SFKs in Eph-mediated LMC motor axon guidance. In summary, our findings demonstrate that SFKs are essential for motor axon guidance and suggest that they play an important role in relaying ephrin:Eph signals that mediate the selection of motor axon trajectory in the limb.

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Received Jan. 16, 2009; revised March 16, 2009; accepted April 1, 2009.

Correspondence should be addressed to Artur Kania, Institut de recherches cliniques de Montréal, 110, avenue des Pins Ouest, Montréal, QC H2W 1R7, Canada. Email: artur.kania{at}ircm.qc.ca

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