Cyclin-dependent kinase 5 (Cdk5) and its activator p35 are critical for radial migration and lamination of cortical neurons. However, how this kinase is regulated by extracellular and intracellular signals during cortical morphogenesis remains unclear. Here we show that PKC, a member of novel PKC expressing in cortical neurons, could stabilize p35 by direct phosphorylation. PKC attenuated the degradation of p35 but not its mutant derivative which could not be phosphorylated by PKC Downregulation of PKC by in utero electroporation of specific small interference RNA (siRNA) severely impaired the radial migration of cortical neurons. This migration defect was similar to that caused by downregulation of p35 and could be prevented by co-transfection with the wild type but not mutant p35. Furthermore, PKC could be activated by the pro-migratory factor brain-derived neurotrophic factor (BDNF) and was required for the activation of Cdk5 by BDNF. Both PKCand p35 were required for the pro-migratory effect of BDNF on cultured newborn neurons. Both PKCand p35 were required for the pro-migratory effect of BDNF on cultured newborn neurons. Thus, PKC may promote cortical radial migration through maintaining the proper level of p35 in newborn neurons.