REELIN AND BRAIN-DEVELOPMENT - PROGRESS S INCE THE CLONING OF THE REELIN GENE

Reelin is the protein defective in Reeler mice, which are characterize d by abnormal architectonic development. Reelin is an extracellular ma trix protein specific of the embryonic brain and produced by Cajal-Ret zius cells and a few other cell types. The reelin gene is about 400-45 0 kbp-long and composed of 65 exons; it contains a repeated structure thought to result from gene duplication. Two alternative forms of the reelin mRNA are found, namely facultative inclusion of a 6 nt microexo n or alternative polyadenylation, the function of which is unknown. Mo noclonal antibodies have been produced against both extremities of the protein and allow the study of native Reelin in embryonic brain extra cts. Using these antibodies, the Orleans allele of reeler was shown to result from defective secretion of a truncated Reelin. When Reelin di stribution was studied during development using both immunohistochemis try and in situ hybridization, no correlation was found between expres sion and the reeler phenotype, suggesting that Reelin acts in a juxtac rine fashion in the extracellular matrix, on adjacent target cells. Th e presence of reelin mRNA was demonstrated in the embryonic blain of b irds and reptiles, a finding compatible with the hypothesis that Reeli n played a role in cortical evolution. Recent work showed that mice de ficient in the disabled1 (Dab1) kinase adaptor have a reeler phenotype but express normal amounts of Reelin, and that scrambler/yotari, two mutants with a reeler phenotype, are mutations of Dab1. Furthermore, m ice deficient in the kinase Cdk5 and, to a lesser extent, in its cofac tor p35, also have reeler-like brain anomalies. These findings strongl y implicate a kinase cascade in the transduction of the signal initiat ed by reelin at the level of target neurons.