Scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice

Formation of the mammalian brain requires choreographed migration of neurons to generate highly ordered laminar structures such as those in the cortices of the forebrain and the cerebellum, These processes are severely disrupted by mutations in reelin(1) which cause widespread misplacement of neurons and associated ataxia in reeler mice(2,3). Reelin is a large extracellular protein secreted by pioneer neurons that coordinates cell positioning during neurodevelopment(1,4-8). Two new autosomal recessive mouse mutations, scrambler(9) and yotari(10) have been described that exhibit a phenotype identical to reeler(9-11). Here we report that scrambler and yotari arise from mutations in mdab1 (ref, 12), a mouse gene related to the Drosophila gene disabled (dab)(13). Both scrambler and yotari mice express mutated forms of mdab1 messenger RNA and little or no mDab1 protein. mDab1 is a phosphoprotein that appears to function as an intracellular adaptor in protein kinase pathways, Expression analysis indicates that mdab1 is expressed in neuronal populations exposed to Reelin. The similar phenotypes of reeler, scrambler, yotari and mdab1 null mice(14) indicate that Reelin and mDab1 function as signalling molecules that regulate cell positioning in the developing brain.