The origin and migration of cortical neurons in human and mouse

Abstract

Event Abstract Back to Event The origin and migration of cortical neurons in human and mouse Laura A. Elias1*, David V. Hansen1, Arnold R. Kriegstein1 and Jan H. Lui1 1 University of California, Department of Signal Processing, United States The adult cerebral cortex is composed of excitatory and inhibitory neurons that arise from progenitor cells in disparate proliferative regions in the developing brain and follow different migratory paths. Excitatory pyramidal neurons originate near the ventricle and migrate radially to their positions in the cortical plate. Inhibitory interneurons arise in the ventral telencephalon and migrate tangentially to enter the developing cortex before migrating radially to reach their correct laminar position. Radial glia produce both excitatory and inhibitory neurons indirectly, by generating intermediate progenitor cells that undergo symmetric cell divisions to increase the numbers of nerve cells they produce. In the rodent, intermediate progenitor cells generally reside in a subventricular zone (SVZ). We found that in the embryonic human cortex, very large numbers of neuronal stem and intermediate progenitor cells are produced in a proliferative zone not present in the rodent brain, the outer subventricular zone. The medial ganglionic eminence in the fetal human brain also contains a large SVZ and is the source of large numbers of inhibitory cortical neurons. The oSVZ may account for the very large neocortex size peculiar to humans. Gap junction adhesion has recently been shown to play an important mechanistic role in the radial migration of excitatory neurons. Gap junctions are expressed in stem and progenitor cells of the ventral telencephalon as well as migrating neurons. By allowing communication among progenitors or between progenitors and neuroblasts, gap junctions are thought to play a role in regulating cortical development. We asked whether a gap junction-mediated mechanism governs the tangential or radial migration of inhibitory interneurons. Using shRNA knockdown of Cx43 and Cx26 together with rescue experiments, we found that gap junctions are dispensible for the tangential migration of interneurons, but that Cx43 plays a role in the switch from tangential to radial migration that allows interneurons to enter the cortical plate and find their correct laminar position. Moreover, this action is dependent on the adhesive properties and the C-terminus of Cx43, but not the Cx43 channel. Thus, the radial phase of interneuron migration resembles that of excitatory neuron migration in terms of dependence on Cx43 adhesion. These findings also provide mechanistic support for an interaction between migrating interneurons and radial glia during the switch from tangential to radial migration.