Abstract 999: The role of α-catenin homologue α-catulin during mouse development

Abstract

Abstract In multicellular organisms, cell-cell contacts that are mediated by classical cadherins have essential roles in many fundamental processes, such as morphogenesis, maintenance of tissue integrity, wound healing and cell polarity. Furthermore, there is overwhelming evidence that the adherens junction (AJ) is also an important tumor and/or invasion suppressor and E-cadherin and α-catenin are very often down-regulated during tumor progression. As the primary cell-cell adhesion protein in epithelial cells, E-cadherin has long been studied in cancer progression. Similarly, additional roles for β-catenin in the Wnt signaling pathway have led to many studies of the role of β-catenin in cancer. Alpha-catenin, in contrast, has received less attention. However our recent data demonstrated that conditional loss of α-catenin in skin results in formation of squamous cell carcinoma like phenotype, accompanied by increased proliferation, motility and activation of NF-κB and its proinflammatory target genes, which account for many features of invasive epithelial cancer. The mechanism of this complex phenotype after α-catenin deletion is not well understood. Our new data show that the down-regulation of α-catenin is followed by the up-regulation of α-catenin homologue α-catulin. This protein was shown to interact directly with components of Rho GTPases and NF-κB signaling pathways, both crucial for tumor development and progression, and increase migration and survival of human squamous cell carcinoma cells. Therefore, our goal is to understand the role of α-catulin during normal development and tumor progression and how it influences the classical α-catenin function. Using a gene trap method, we have generated α-catulin KO mice. Straight α-catulin KO results in embryonic lethality, with embryos dieing around 10.5E with neural tube closure defects, craniofacial defects and hemorrhaging in the head. To study α-catulin expression pattern, we used a β-galactosidase reporter tag under endogenous α-catulin promoter, and found α-catulin to be expressed in the neural crest during development and maintained in some structures derived from neural crest cells during adulthood. Microarray analysis performed on α-catulin WT and KO embryos showed the most changes in axon guidance and Rho-mediated actin motility genes. These results led us to look at the role of α-catulin during cell migration. In vitro analyses of α-catulin WT and KO embryoid bodies and endodermal cells showed differential migration rates between the WT and KO cells. In vivo analyses by wound healing in heterozygous α-catulin mice showed an increase in α-catulin expression during wound healing. In addition, immunofluorescence staining showed α-catulin co-localized with actin cytoskeleton at the leading edge of the migrating cell. To summarize, α-catulin KO embryos have severe phenotypes and evidence suggests that α-catulin may play a role in migration during development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 999.