Investigating Cdk5 and Abl - signaling partners in Drosophila axon guidance. M.L. Fluegel ^{1, 2}, E. Giniger ¹. 1) Fred Hutchinson Cancer Research Center, Seattle, WA; 2) Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA.

   Cdk5, a member of the cyclin dependent kinase family, has been shown to play a role in synaptic function, neuronal migration, and axon guidance in mice. We have shown that Cdk5 functions in axon guidance decisions in Drosophila. Cdk5 possesses activity only in post-mitotic neurons due to the expression pattern of its only known Drosophila activator, p35. The pathways that Cdk5 functions within are unclear, and its regulators are not known. There is evidence in mice for Cdk5 activation by the tyrosine kinase Abl through a phosphorylation event on Tyr15 of Cdk5. Abl, like Cdk5, has a role in axon patterning, but the pathways that utilize its activity are not known. Disabled (Dab) acts as an Abl adaptor, while Enabled (Ena) and Dlar function as Abl antagonists. We are investigating the Abl/Cdk5 pathway and its role in Drosophila axon patterning through both biochemical and phenotypic means.
   We have generated a p35 mutant that confirms our previous observations of axon guidance defects through use of a Cdk5 kinase dead transgene. Moreover, we see a shortened lifespan in the homozygous mutant flies. Interestingly, heterozygosity for Dab suppresses the lifespan phenotype, contrary to the predictions of the Abl/Cdk5 model. In addition, we have not seen increased activity or phosphorylation of Cdk5 in an Abl gof setting in biochemical experiments. These data present the possibility that Abl and Cdk5 function in parallel pathways to control axon guidance. We are currently pursuing phenotypic experiments to determine if Abl mutants modify the known Cdk5 phenotypes.