The cerebral cortex consists of six neuronal layers that share common birthdate, axonal targets and gene expressions. Within the neocortex, two major types of neurons exists: excitatory pyramidal neurons and inhibitory interneurons. During development, pyramidal neurons are generated from progenitor cells within the ventricular zone and move toward the surface of the cortical plate, where they terminate migration and undergo morphological changes to establish specific dendritic patterns. Although it is considered that several proteins are involved in these steps of cortical neuron differentiation, the mechanisms by which the positioning and dendritic patterns of neocortical layer subtypes are determined remain largely unknown.
Recently studies in Drosophila have indicated that axon guidance molecules are also involved in dendrite patterning. Here, we focused on an axon guidance molecule; Roundabout (Robo). Robo was initially identified as a receptor for the secreted ligand Slits. They mediate commissural axon guidance in both vertebrate and invertebrate nervous systems. In the neocortex, Robo signaling is also required for the proliferation and migration of interneurons. Recently, we identified that Robo1 plays key roles in radial migration and laminar distribution of upper-layer pyramidal neurons of the mouse neocortex. Using Robo1 knockout mice and conditional Robo1 suppression, we demonstrate that Robo1-suppressed pyramidal neurons undergo significant changes in their morphology during the early postnatal period. We further assessed the requirement of ligand-mediated Robo1 signaling in the development of neocortical pyramidal neurons, by generating single and compound knockout mice for Slits. Our results demonstrate distinctive roles of Robo/Slit signaling in the laminar distribution and dendritic development of neocortical pyramidal neurons, indicating that the mechanisms by which neocortical neurons are navigated to their final positions and establish layer-specific dendritic patterns during development require combinatorial action of axon guidance molecules.