Human Molecular Genetics Advance Access published online on April 6, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl093
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1 Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto. Porto 4150-180, Portugal.; Centro Andaluz de Biología del Desarrollo (CABD), CSIC-JA-Universidad Pablo de Olavide. Ctra. de Utrera km1, Seville 41013, Spain.
* To whom correspondence should be addressed. Germline mutations in the human E-Cadherin gene, CDH1, are initiating events in cases of human hereditary diffuse gastric cancer (HDGC) indicating that hE-cadherin (hEcad) is a tumor suppressor. Among the hEcad mutations identified so far, some are missense, but the pathological relevance of these missense mutants is still unclear. In vitro assays show that missense mutations result in full-length hEcad molecules that retain some distinct biological activity, but in vivo functional studies in animal models are still lacking. Here we verify the potential of a Drosophila model to in vivo characterize the functional consequences of HDGC-associated germline missense mutations and to identify signaling pathways affected by these mutations. To this end, we have generated transgenic fly strains expressing the wild-type human E-cadherin gene or its missense mutations. Similarly to the fly E-cadherin, expression of wild-type hEcad and missense forms in fly epithelia resulted in their localization to the subapical region. In addition, we verify a genotype-phenotype correlation associated to the specific domain affected by the mutations, because cells expressing normal or missense mutant hEcad display different migratory and invasive behaviors in fly epithelia. We show that some of these effects might be mediated through hEcad interacting with the endogenous fly ß-catenin, Armadillo, thus interfering with the Wnt signaling pathway. Therefore, the use of this simple in vivo system will contribute to characterize the effects that missense hEcad have on cell behavior in a tissue environment, and might help to understand their significance in gastric cancer onset.
Received March 1, 2006
Revised March 29, 2006
Accepted March 29, 2006
Article
E-cadherin missense mutations, associated with Hereditary Diffuse Gastric Cancer (HDGC) syndrome, display distinct invasive behaviours and genetic interactions with the Wnt and Notch pathways in Drosophila epithelia
Paulo Pereira 1,
Alexandra Teixeira 2,
Sofia Pinho 3,
Paulo Ferreira 4,
Joana Fernandes 3,
Carla Oliveira 4,
Raquel Seruca 4,
Gianpaolo Suriano 4,
and
Fernando Casares 1 *
2 Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto. Porto 4150-180, Portugal.
3 Centro Andaluz de Biología del Desarrollo (CABD), CSIC-JA-Universidad Pablo de Olavide. Ctra. de Utrera km1, Seville 41013, Spain.
4 Institute of Molecular Pathology and Immunology (IPATIMUP), Universidade do Porto. Porto 4200-465, Portugal.
Fernando Casares, E-mail: fcasfer{at}upo.es
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