The reeler mouse: Anatomy of a mutant

The neurological mouse mutant reeler is characterized by, ataxia and disruption of cellular layers in the brain. Tins mutant has long been studied as a model to Understand how cortical structures of the vertebrate brain are formed during development. The reeler phenotype arises from homozygous loss-of-function mutations in reelin, a gene that encodes an extracellular glycoprotein secreted by distinct neuronal populations during embryonic and postnatal brain development. Reelin is a key regulator of cortical development that appears to function as a switch, causing neurons to terminate their migration phase and to begin the assembly of cortical layers. The Reelin signal is interpretcd by neurons and neuronal progenitors through signal transducing molecules, such as the VLDLR and the ApoER2 receptors, and the Dab I adapter protein. Loss of these essential transducers in mutant mice results in the appearance of a phenotype indistinguishable from reeler. Much has been learned during the past few years about the molecular mechanisms that rnediate the Reelin signal. This large protein is thought to cluster the VLDLR and ApoER2 receptors, thereby activating src-family kinases that phosphorylate Dab I on tyrosine residues. This event in turn causes Dahl to interact with a variety of signal transduction molecules and proteins that regulate cytoskeleton dynamics, before being degraded 1)), the proteosome pathway. Expression of Reelin and its transduction machinery continues long after migration is complete and may affect neuronal maturation and synaptic connectivity, in the postnatal brain. Despite the tremendous progress made in this past decade, the whole spectrum of Reelin activities in brain development and its relevance to human cognitive disorders has yet to be fully unraveled.