Neuronal Migration: Integrating New Neurons
One of the most prominent anatomical features of the neocortex is its laminar organization, in which neurons with similar properties are segregated into specific cell layers that allow connections to be made efficiently. Importantly, none of the cortical cell types are actually generated locally within the cerebral cortex proper, but are made in distant germinal zones from where they migrate into the cortex. Therefore, the precise organization of the cerebral cortex depends on coordinated cycles of cell-fate specification, neurogenesis and neuronal migration. One of the best-known signaling molecules required for neuronal migration and cortical layer formation is Reelin. Mutations in Reelin signaling cause severe cortical abnormalities in humans and mice, including lissencephaly and disorganized layers. Reelin is a secreted glycoprotein that binds to receptors on the surface of migrating neurons, thereby inducing phosphorylation of the cytoplasmic adaptor protein Dab1. This event recruits several downstream signaling molecules, but the cellular functions that are regulated by these effectors are not well understood. While it is generally accepted that Reelin signaling regulates neuronal migration, contrasting models have been proposed for the cellular mechanisms of how Reelin controls cell motility and layer formation. For example, Reelin has been proposed to act as a chemoattractant, repellent, stop or detachment signal for migrating neurons. This controversy is compounded by the fact that neuronal migration is actually the sum of several distinct types of cell motility, each of which is likely to be controlled by different signaling pathways. Furthermore, different subtypes of projection neurons use distinct modes of migration depending on their target destination.
Our lab has helped define the cellular mechanisms of Reelin function in cortical lamination and elucidate the molecular pathway downstream of Reelin signaling during neuronal migration. Using precisely timed conditional knockout of Dab1 in migrating neurons, we found that Reelin signaling is essential only for a specific type of migration, called glia-independent somal translocation. While it is widely accepted in the field that disturbances in other modes of migration cause cortical lamination defects, these findings demonstrate that loss of glia-independent migration is equally disruptive. We further demonstrated that Reelin signaling promotes translocation of neurons by stabilizing their leading processes at the top of the cortex, by a mechanism involving Cadherin- and Nectin-dependent adhesions.
Our lab has helped define the cellular mechanisms of Reelin function in cortical lamination and elucidate the molecular pathway downstream of Reelin signaling during neuronal migration. Using precisely timed conditional knockout of Dab1 in migrating neurons, we found that Reelin signaling is essential only for a specific type of migration, called glia-independent somal translocation. While it is widely accepted in the field that disturbances in other modes of migration cause cortical lamination defects, these findings demonstrate that loss of glia-independent migration is equally disruptive. We further demonstrated that Reelin signaling promotes translocation of neurons by stabilizing their leading processes at the top of the cortex, by a mechanism involving Cadherin- and Nectin-dependent adhesions.
