ApoER2 Controls not only neuronal migration in the intermediate zone but also termination of migration in the developing cerebral cortex

Abstract

Neuronal migration contributes to the establishment of mammalian brain. The extracellular protein Reelin sends signals to various downstream molecules by binding to its receptors, the apolipoprotein E receptor 2 (ApoER2) and very low-density lipoprotein receptor and exerts essential roles in the neuronal migration and formation of the layered neocortex. However, the cellular and molecular functions of Reelin signaling in the cortical development are not yet fully understood. Here, to gain insight into the role of Reelin signaling during cortical development, we examined the migratory behavior of Apoer2-deficient neurons in the developing brain. Stage-specific labeling of newborn neurons revealed that the neurons ectopically invaded the marginal zone (MZ) and that neuronal migration of both early- and late-born neurons was disrupted in the intermediate zone (IZ) in the Apoer2 KO mice. Rescue experiments showed that ApoER2 functions both in cell-autonomous and noncell-autonomous manners, that Rap1, integrin, and Akt are involved in the termination of migration beneath the MZ, and that Akt also controls neuronal migration in the IZ downstream of ApoER2. These data indicate that ApoER2 controls multiple processes in neuronal migration, including the early stage of radial migration and termination of migration beneath the MZ in the developing neocortex.