Synergistic contributions of cyclin-dependant kinase 5/p35 and Reelin/Dab1to the positioning of cortical neurons in the developing mouse brain

Cyclin-dependent kinase (Cdk) 5 is a unique member of the Cdk family, becau se Cdk5 kinase activity is detected only in the nervous tissue. Two neuron- specific activating subunits of tdk5, p35 and p39, have been identified. Ov erlapping expression pattern of these isoforms in the embryonic mouse brain and the significant residual Cdk5 kinase activity in brain homogenate of t he p35-/- mice indicate the redundant functions of the Cdk5 activators in v ivo. Severe neuronal migration defects in p35-/-Cdk5 +/- mice further suppo rt the idea that the redundant expression of the Cdk5 activators may cause a milder phenotype in p35-/- mice compared with Cdk5-/- mice. Mutant mice l acking either Cdk5 or p35 exhibit certain similarities with Reelin/Dab1-mut ant mice in the disorganization of cortical laminar structure in the brain. To elucidate the relationship between Cdk5/p35 and Reelin/Dab1 signaling, we generated mouse lines that have combined defects of these genes. The add ition of heterozygosity of either Dab1 or Reelin mutation to p35-/- causes the extensive migration defects of cortical neurons in the cerebellum. In t he double-null mice of p35 and either Dab1 or Reelin, additional migration defects occur in the Purkinje cells in the cerebellum and in the pyramidal neurons in the hippocampus. These additional defects in neuronal migration in mice lacking both Cdk5/p35 and Reelin/Dab1 indicate that Cdk5/p35 may co ntribute synergistically to the positioning of the cortical neurons in the developing mouse brain.