Activation of cyclin-dependent kinase 5 is involved in axonal regeneration.

Cyclin-dependent kinase 5 (Cdk5) is a serine-threonine kinase that is activated by the binding of p35 or p39 regulatory protein. Cdk5 and p35 are highly localized in the growth cone of cultured neurons, and Cdk5 activity is associated with neurite outgrowth. Here we report evidence on the functional involvement of Cdk5 kinase in regenerating peripheral nerve fibers. Elevated levels of Cdk5 protein were found in regenerating axons of facial motor neurons after nerve crush, and Cdk5 kinase activity was increased with a similar time course as increases in Cdk5 protein levels. The p35 protein was also found to be associated with increased Cdk5 activity in regenerating nerves. Administration of Cdk5 inhibitors, roscovitine and olomoucine, into the crushed nerves resulted in decreases in Cdk5 kinase activity in nerves and retardation of nerve fiber regrowth. Retardation of axonal regeneration by Cdk5 inhibition was confirmed by reduced labeling of facial motor neurons using retrograde tracer fluorogold (FG). These findings provide first in vivo evidence indicating that Cdk5 activity, which is induced by axonal injury, may play an important role in axonal regeneration.