Dishevelled is one of several segment polarity genes required for the wingless signal transduction pathway in Drosophila. This developmental pathway appears to be conserved in the mouse, where mutations in murine orthologs of this pathway result in a variety of specific abnormalities. Three murine dishevelled genes Dvl-1, Dvl-2 and Dvl-3, have been isolated. All three Dvl genes are expressed in a similar pattern in embryos and adults. To address the function of these genes during mammalian development, we have generated mice with targeted disruptions of each of the Dvl genes. Mice homozygous for a null allele of Dvl-1 are viable and fertile, with novel behavioral abnormalities, indicating abnormal social interaction, depressed startle responses, and sensorimotor gating abnormalities. Mice homozygous for a null allele of Dvl-2 survive to adulthood and are fertile, but are born in reduced numbers from heterozygous Dvl-2 crosess. Preliminary data suggest that double homozygotes for Dvl-1 and Dvl-2 are non- viable and that Dvl-1 homozygotes/Dvl-2 heterozygotes and Dvl-1 heterozygotes/Dvl-2 homozygotes are born in reduced numbers. Dvl-3 germ line chimeras have been produced. Matings to analyze the phenotypes of double and triple mutants of the Dvl gene family are in progress. To genetically analyze this important, conserved developmental pathway, we have crossed Dvl-1 mutant mice with transgenic mice that develop mammary adenocarcinomas under the influence of a Wnt-1 transgene and Wnt-3a vestigial tail hypomorph. Loss of Dvl-1 function has no effect on either phenotype. These results suggest that there is functional redundancy among the three Dvl genes in mice.
