Reelin mouse mutants as models of cortical development disorders

Developmental defects in neuronal positioning and synaptic connectivity are commonly found in neurological diseases, and they are believed to underlie many cognitive and affective disorders. Several mouse mutants are currently available that model at least some aspects of human developmental brain disorders. With the identification of the genes mutated in these animals and the study of the cellular basis of the phenotypes, we have taken significant strides toward an understanding of the mechanisms controlling proper brain development and the consequences of their dysfunction. In particular, mouse mutants deficient in the Reelin gene have provided valuable insights into the mechanisms of cortical development. Absence of Reelin expression in the spontaneous mutant mouse reeler leads to extensive defects in neuronal position and dendrite development. In humans, loss of Reelin results in a type of lissencephaly with severe cortical and cerebellar malformation. Genetic and biochemical studies using mouse mutants suggest that the Lis1 protein may participate in the Reelin signaling pathway controlling cortical development. Reduced levels of Reelin are also present in postmortem brains of patients with schizophrenia, suggesting a possible link with this cognitive disorder. The regulation of the Reelin gene may thus provide insights into the mechanisms of this disease.