ABERRANT SPLICING OF A MOUSE DISABLED HOMOLOG, MDAB1, IN THE SCRAMBLER MOUSE

Although accurate long-distance neuronal migration is a cardinal featu re of cerebral cortical development, little is known about control of this migration. The scrambler(scm) mouse shows abnormal cortical lamin ation that is indistinguishable from reeler. Genetic and physical mapp ing of scm identified yeast artificial chromosomes containing an exon of mdab1, a homolog of Drosophila disabled, which encodes a phosphopro tein that binds nonreceptor tyrosine kinases. mdab1 transcripts showed abnormal splicing in scm homozygotes, with 1.5 kb of intracisternal A particle retrotransposon sequence inserted into the mdab1 coding regi on in antisense orientation, producing a mutated and truncated predict ed protein. Therefore, mdab1 is most likely the scm gene, thus implica ting nonreceptor tyrosine kinases in neuronal migration and lamination in developing cerebral cortex.