Mutations (primarily somatic) of human AXIN1 and AXIN2 have been found in a number of cancers. AXIN1 encodes a scaffolding protein for the multiprotein beta-catenin destruction complex, which drives the phosphorylation and subsequent proteolysis of the transcriptional regulator β-catenin. There is a single Axin in Drosophila, encoded by Dmel\Axn, for which classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
Neither human gene, AXIN1 nor AXIN2, has been introduced into flies.
Animals homozygous for loss-of-function mutations of Dmel\Axn typically die during the embryonic stage. In wing discs, somatic clones of Axn loss-of-function mutations exhibit an overgrowth phenotype at the expense of surrounding wild-type tissue.
Work in flies has focused on characterization of variants analogous to disease-associated variants found in AXIN1. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): V72R in the fly Axn gene (corresponds to L106R in the human AXIN1 gene); L67P in the fly Axn gene (corresponds to L101P in the human AXIN1 gene). The Axn L67P mutation has only mild effects. The V72R mutation results in phenotypes observed for Axn loss-of-function mutations: animals homozygous for the V72R mutation die at early developmental stages; in wing discs, somatic clones of Axn carrying the V72R variant exhibit an overgrowth phenotype at the expense of surrounding wild-type tissue. In human, the L106R variant has been observed as somatic mutation in hepatocellular carcinoma (Taniguchi, et al., 2002; pubmed:12101426).
The fly genes Apc and Apc2, which encode components of the beta-catenin destruction complex (see FBgg0000896), are orthologous to human APC. As is observed for Axn, somatic clones mutant for Apc/Apc2 result in overgrowth due to the elimination of surrounding wild-type cells. APC is implicated in familial adenomatous polyposis 1; this disease has also been modeled in flies (see FBhh0000135).
Work done in human cells has pointed to destabilization of the AXIN1 protein and subsequent self-aggregation as a pathological mechanism for specific missense mutations; work in Drosophila supports this hypothesis. A Dmel\Axn transgene carrying both the V72R variant and mutation of the 'aggregon' site was tested. Animals carrying the double mutant survive up to the adult stage at 18 degrees C; somatic clones exhibit a reduced overgrowth phenotype.
[updated May 2019 by FlyBase; FBrf0222196]