Molecular mechanisms regulating the intracortical migration of interneurons

Abstract

The cerebral cortex is composed of two main types of neurons, inhibitory GABAergic interneurons and excitatory glutamatergic pyramidal cells. These two major classes of cortical neurons are generated in different and distant proliferative regions in the developing brain and follow diverse strategies to reach their final position. While pyramidal cells are born in the ventricular zone of the dorsal telencephalon, interneurons originate in the ganglionic eminences and migrate longer distances to populate the cortex. Since disruption in the migration of GABAergic interneurons leads to defects in the organization of the adult cortex, understanding the mechanisms that control the guided migration of cortical interneurons from their origin to their final location is fundamental to improve our knowledge of the cerebral cortex in health and disease. The mechanisms regulating the tangential migration of interneurons from their subpallial origin to the developing cortex have been extensively elucidated. In contrast, the processes and molecules controlling their distribution and final integration within the cerebral cortex remain unidentified. Here, we have investigated the mechanisms regulating the entry of interneurons into the developing cortical plate, in which pyramidal cells are being organized into specific layers. We have used a candidate approach to unravel the mechanisms that regulate the switch in the mode of migration of interneurons from tangential to radial. We searched for significant differences in a set of genes that play a role in cell migration, adhesion, and axon guidance and that are expressed in the developing cortical plate at relevant stages. We found that Neuregulin-3 (Nrg3), a member of the neuregulin family of genes, is highly expressed in pyramidal cells in the developing cortical plate since its inception, and is maintained in pyramidal cells as they mature. Our experiments revealed that Nrg3 is a potent short-range chemoattractant for MGE-derived interneurons, which therefore contribute to their normal allocation within the cortex. Gain and loss of function studies are consistent with this notion, reinforcing the idea that the timed entry of interneurons in the developing cortical plate is required for their normal lamination. To shed some light into the mechanisms controlling the final laminar position of MGE-derived interneurons, we took an unbiased approach through gene profiling analyses in whole genome Affimetrix® arrays. We identify a set of genes that are differentially expressed before and after interneurons allocate into their final position in the cortex. Functional analysis of one of these candidates, the chemokine Cx3cl1, revealed that this factor does not seem to be fundamental for the regulation of this process.