Role of Reelin in the Control of Brain Development

Reeler is an autosomal recessive mutation in mice that results in widespread disruption of laminated regions of the brain. We isolated a gene, reelin, that is mutated in reeler mice. The protein product of reelin has features of extracellular matrix components and it is expressed in a temporal and spatial pattern during embryonic and postnatal development consistent with the phenotypic defects in reeler mice. To understand the molecular basis of the function of Reelin, we constructed a full length reelin clone and used it to direct Reelin expression. Using this clone we found that Reelin is a secreted glycoprotein and that a highly charged C-terminal region is essential for secretion. Furthermore, we demonstrated that an amino acid sequence present in the N-terminal region of Reelin contains an epitope that is recognized by the CR-50 monoclonal antibody. CR-50 was raised against an antigen expressed in normal mouse brain that is absent in reeler mice. The interaction of CR-50 with its epitope has been shown to disrupt neuronal migration in vitro and in vivo. We used CR-50 to precipitate p385 Reelin from reticulocyte extracts programmed with reelin mRNA, from cells transfected with reelin clones and from cerebellar explants. Reelin appears to function as an instructive signal in the regulation of cell patterning during development.