Regulation of N-cadherin-mediated adhesion by the p35-Cdk5 kinase

Background: The p35-Cdk5 kinase has been implicated in a variety of functio ns in the central nervous system (CNS), including axon outgrowth, axon guid ance, fasciculation, and neuronal migration during cortical development, In p35(-/-) mice, embryonic cortical neurons are unable to migrate past their predecessors, leading to an inversion of cortical layers in the adult cort ex. Results: In order to identify molecules important for p35-Cdk5-dependent fu nction in the cortex, we screened for p35-interacting proteins using the tw o-hybrid system. In this study. we report the identification of a novel int eraction between p35 and the versatile cell adhesion signaling molecule bet a-catenin. The p35 and beta-catenin proteins interacted in vitro and coloca lized in transfected COS cells. In addition, the p35-Cdk5 kinase was associ ated with a beta-catenin-N-cadherin complex in the cortex. In N-cadherin-me diated aggregation assays, inhibition of Cdk5 kinase activity using the Cdk 5 inhibitor roscovitine led to the formation of larger aggregates of embryo nic cortical neurons. This finding was recapitulated in p35(-/-) cortical n eurons, which aggregated to a greater degree than wild-type neurons. In add ition, introduction of active p35-Cdk5 kinase into COS cells led to a decre ased beta-catenin-N-cadherin interaction and loss of cell adhesion. Conclusions: The association between p35-Cdk5 and an N-cadherin adhesion co mplex in cortical neurons and the modulation of N-cadherin-mediated aggrega tion by p35-Cdk5 suggests that the p35-Cdk5 kinase is involved in the regul ation of N-cadherin-mediated adhesion in cortical neurons. (C) 2000 Elsevie r Science Ltd. All rights reserved.