SURFACE MEDIATED MECHANISMS OF NEURONAL MIGRATION

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Neuronal migration is an extraordinary event which insures that postmitotic neurons generated in the embryonic ventricular zone acquire their proper positions in the mature brain and establish their adult phenotypic identities. In the mammalian embryo, most postmitotic neurons destined to form the cerebral cortex reach their permanent residences by following along the surface of elongated fibers that have been identified as transient radial glial cells. This project analyzed the molecular mechanisms of this dynamic process by focusing ont he molecular bonds that attract and adhere neurons to glia during migration. Using polyclonal antibodies (D4) to antigens on radial glial cells made in the previous cycle of this grant and two new mouse monoclonal antibodies (14D7 and 19G11), we have demonstrated the presence of two distinct "microdomain" antigens of 48 kD and 72 kD molecular weight on the free surface of radial glial cells in the embryonic cerebral wall in vitro. Up to now, these are the only identified recognition molecules isolated from the glial side of the neuron-glia junction. Here we propose to characterize further the emergence, distribution, and function of these polypeptides in the embryonic cerebral wall of living embryos. To attain this challenging goal, we propose the following logic for our studies: 1) examine expression and localization of the glial cell surface microdomain proteins at various stages during neuronal migration in vivo: 2) study the modulation of neuronal migration by antibodies to glial cell surface microdomains; 3) characterize glial cell surface microdomain proteins and identify the corresponding receptor molecules on the neuronal side of the microdomain junctions. We have all the necessary methods, personnel and equipment as well as a unique battery of antibodies to identified glial cell surface antigens to address these goals. These studies offer an opportunity to obtain a comprehensive view of the molecular mechanisms underlying the critical development event of neuronal migration and to gain insight into the pathogenesis of a variety of migratory disorders that underlie cortical (and subcortical) malformations.