Dishevelled-1 <p>Wnt proteins constitute a large family of secreted signalling molecules thatare involved in intercellular signalling during development. The name derives from the first 2 members of the family to be discovered: int-1 (mouse) and wingless (Wg) (Drosophila) [<cite idref="PUB00011232"/>]. It is now recognised that Wnt signalling controls many cell fate decisions in a variety of different organisms, including mammals. Wnt signalling has been implicated in tumourigenesis, early mesodermal patterning of the embryo, morphogenesis of the brain and kidneys, regulation of mammary gland proliferation and Alzheimer's disease [<cite idref="PUB00011233"/>].</p><p>Wnt signal transduction proceeds initially via binding to their cellsurface receptors - the so-called frizzled proteins. This activates thesignalling functions of B-catenin and regulates the expression of specificgenes important in development [<cite idref="PUB00011234"/>]. More recently, however, several non-canonical Wnt signalling pathways have been elucidated that act independently of B-catenin. In both cases, the transduction mechanismrequires dishevelled protein (Dsh), a cytoplasmic phosphoprotein that actsdirectly downstream of frizzled [<cite idref="PUB00011235"/>]. In addition to its role in Wnt signalling, Dsh is also involved in generating planar polarity in Drosophila and has been implicated in the Notch signal transduction cascade. Three human and mouse homologues of Dsh have been cloned (DVL-1 to 3); it is believed that these proteins, like their Drosophila counterpart, are involved in signal transduction. Human and murine orthologues share more than 95% sequence identity and are each 40-50% identical to Drosophila Dsh.</p><p>Sequence similarity amongst Dsh proteins is concentrated around three conserved domains: at the N terminus lies a DIX domain (mutations mapping to this region reduce or completely disrupt Wg signalling); a PDZ (or DHR) domain, often found in proteins involved in protein-protein interactions, lies within the central portion of the protein (point mutations within this module have been shown to have little effect on Wg-mediated signal transduction); and a DEP domain is located towards the C terminus and is conserved among a set of proteins that regulate various GTPases (whilst genetic and molecular assays have shown this module to be dispensable for Wg signalling, it is thought to be important in planar polarity signalling in flies [<cite idref="PUB00011235"/>]).</p><p>Mouse DVL-1 was first cloned in 1994 [<cite idref="PUB00011561"/>], followed by the human orthologuein 1997. The human and murine DVL-1 genes encode polypeptides of 670 and695 amino acids respectively. Murine DVL genes are ubiquitously expressedduring development, displaying extensive redundancy in spatial and temporalexpression. In the mouse embryo, DVL-1 is expressed most abundantly in thecentral nervous system.</p>