Selective expression of doublecortin and LIS1 in developing human cortex suggests unique modes of neuronal movement

Abstract

The genes doublecortin (DCX) and LIS1 are required for proper cortical neuronal migration and differentiation in humans. Here, we study the expression pattern of the encoded proteins of these genes in developing human brain. LIS1 stained virtually all migrating neurons throughout periods of development. Initially, DCX extensively overlapped with Reelin in early preplate stage in radially oriented columns of cells in the ventricular zone, whereas at later stages, the majority of DCX-positive cells were horizontally oriented. During the cortical plate stage, two opposite patterns of DCX expression were found: in radially oriented apical processes, presumably of pyramidal cells in the cortical plate, and in non-radially oriented mono- or bipolar neurons with migratory morphologies in the deep compartments of the cerebral wall. The extensive colocalization of DCX and Calretinin in non-radially oriented neurons suggested a non-pyramidal phenotype. These cells assumed a more vertical orientation upon entering the subplate. In addition, DCX was expressed by cells in the subpial granular layer and by Cajal-Retzius cells. In a 19 week human fetal cortex with a LIS1 mutation, the number of Reelin-expressing Cajal-Retzius cells was reduced and their morphology was abnormal. DCX was expressed by cells in all regions, but in extremely low numbers, suggesting that LIS1 deficiency adversely affects the migration and differentiation of DCX- and Reelin-positive neurons.