Expression of cyclin-dependent kinase 5 (Cdk5) gradually increases during embryonal development until it reaches maximal levels that persist in the adult brain. Cdk5 represents a key component in the reelin signalling cascade. Activity of p35/Cdk5 is critical for the development of normal, six-layered structure of the mammalian brain cortex. Although it is not required for splitting of the cortical pre-plate into the marginal zone and sub-plate, a process that is affected in absence of the reelin and/or Dab1, it is substantial for the later-born neurons to bypass sub-plate neurons and to enter into the embryonal cortical plate. The defect of p35/Cdk5 disrupts the classical inside-out histogenetic pattern of neocortex. Neurons that fail to migrate past older layers of cells accumulate beneath the sub-plate thus forming an abnormal, inverted outside-in configuration in p35/Cdk5 defective animals. Exploration of neuronal migration disturbancies can shednewlight on some diseases ofhuman brain development including different heterotopias and lissencephaly. From an evolutionary point of view, the involvement of Cdk5 in the reelin signalling cascade could define a new step in the brain gray matter development.

        Key words: neuronal migration, reelin, scrambler, yotari, Cdk5, p53, Dab1, cadherin, positive selection of neurons