Synapsin III (SynIII) is a phosphoprotein that is highly expressed at early 
stages of neuronal development. Whereas in vitro evidence suggests a role for 
SynIII in neuronal differentiation, in vivo evidence is lacking. Here, we 
demonstrate that in vivo downregulation of SynIII expression affects neuronal 
migration and orientation. By contrast, SynIII overexpression affects neuronal 
migration, but not orientation. We identify a cyclin-dependent kinase-5 (CDK5) 
phosphorylation site on SynIII and use phosphomutant rescue experiments to 
demonstrate its role in SynIII function. Finally, we show that SynIII 
phosphorylation at the CDK5 site is induced by activation of the semaphorin-3A 
(Sema3A) pathway, which is implicated in migration and orientation of cortical 
pyramidal neurons (PNs) and is known to activate CDK5. Thus, fine-tuning 
of SynIII expression and phosphorylation by CDK5 activation through Sema3A 
activity is essential for proper neuronal migration and orientation.