Evidence that Sema3A and Sema3F regulate the migration of GABAergic neurons in the developing neocortex

Abstract

The ganglionic eminence (GE) supplies neurons containing gamma-aminobutyric acid (GABA) to the pallium of the telencephalon. We investigated the molecular guidance mechanisms of GE cell migration in the neocortex and found neuropilin-1 (Npn-1) or neuropilin-2 (Npn-2) on the GE cells. Ectopic Sema3A or -3F expression by COS1 cell clusters placed on embryo neocortical slices reduced the cell migration but did not block it completely. However, the cell migration was almost completely blocked by COS1 cell clusters expressing both Sema3A and -3F. The direction of cell migration could be reversed by placing Sema3A- and -3F-coexpressing COS1 cell clusters at the distal cut end of the neocortical slices. Further slice experiments revealed that migration of half of the GE cells in the neocortex was regulated by Sema3A and that migration of the other half of the GE cells in the neocortex was regulated by Sema3F. When the cells responding to Sema3A were diverted by ectopic Sema3A expression in vivo, Dlx2-positive cells were found predominantly in the lower intermediate zone (IZ). When the cells responding to Sema3F were diverted by ectopic Sema3F expression in vivo, Dlx2-positive cells were found predominantly in the upper IZ. It was speculated that the semaphorin-neuropilin interactions distribute the GABAergic GE cells evenly in the neocortex as well as guide the GE cells from the GE to the neocortex. The Sema3A expression site under the subplate extended dorsally as the embryo developed. The Sema3A expression seemed to block the Npn-1-positive GE cells in the neocortex from entering the cortical plate (CP) and guide them to the dorsal cortex and the hippocampus. Sema3F expression in the CP continued through the embryonic stages. The expression seemed to block Npn-2-positive GE cells in the neocortex from entering the CP and make them migrate into the lower IZ. Finally, the semaphorin-neuropilin interactions sorted GABAergic inteneurons into the CP and white matter neurons into the IZ.