Disruption of the laminar architecture of the neocortex is associated with more than 25 human neurological disorders, including epilepsy, schizophrenia, autism and mental retardation. Cortical layers are established by the migration of neurons from proliferative zones into the developing cortical wall. Thus, knowledge of how neuronal migration is regulated is critical for elucidating the mechanisms by which layer formation is achieved, and will likely provide insights into the pathological changes associated with several neurological disorders. My long-term objective is to define the mechanisms that control development of the laminar structure of the cerebral cortex. As a first step, I propose here to study the mechanisms by which reelin controls the formation of cortical cell layers. The central hypothesis of my proposal is that reelin targets distinct cellular functions in RGCs and migrating neurons that ultimately control cortical lamination. To test this hypothesis, the following specific alms will be pursued: Aim 1: Determine the mechanisms by which reelin affects RGC behavior. The proposed methods for achieving this goal are: (i) develop based on CRE/LOX recombination, siRNA expression and in utero gene transfer to perturb reelin signaling in RGCs without affecting signaling to neurons, (ii) use real-time imaging to determine the cell-autonomous defects in RGC process outgrowth and attachment that result from inactivation of reelin signaling, (iii) determine the extent to which defects in RGCs secondarily affect migration of cortical neurons, (iv) target cell-surface receptors implicated in reelin signaling to determine their roles in RGC function. Aim 2: Determine the mechanism by which reelin controls the migratory behavior of cortical neurons. The proposed methods for achieving this goal are: (i) use strategies similar to those described in Aim 1 to selectively inactivate reelin signaling in migrating neurons and study effects on their behavior, such as motility, development of polarity and somal translocation, (ii) developed mutant mouse lines suitable for selective genetic perturbation of reelin signaling in early- or late-born neurons, (iii) test the extent to which inactivation of reelin signaling during different modes of migration affects cortical lamination. Relevance: Abnormal development of the cerebral cortex causes more than 25 different human neurological syndromes that are characterized by significant clinical symptoms, including epilepsy, autism, schizophrenia and mental retardation. Therefore, understanding how the cerebral cortex is formed during development of the brain is expected to provide important information on the pathology of these diseases.

F32NS060355

2009-08-01

2012-07-31