Induction of epithelial mesenchimal transition and vasculogenesis in the lenses of Dbl oncogene transgenic mice

• Published in: PloS one Vol. 4; no. 9; p. e7058
• Main Authors: Fardin, Paolo, Ognibene, Marzia, Vanni, Cristina, De Santanna, Amleto, Varesio, Luigi, Eva, Alessandra
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 16.09.2009; Public Library of Science (PLoS)
• Subjects: Aberration; Angiogenesis; Animals; Apoptosis; Cataracts; Cell Biology; Cell Biology/Cell Adhesion; Cell Biology/Cell Growth and Division; Cell Biology/Cytoskeleton; Cell Biology/Extra-Cellular Matrix; Cell Biology/Gene Expression; Cell Biology/Morphogenesis and Cell Biology; Cell Differentiation; Cell growth; Cell migration; Cell Movement; Cell Proliferation; Coding; Colorectal cancer; Developmental disabilities; Differentiation; Disruption; DNA microarrays; Epithelial cells; Epithelium - metabolism; Female; G proteins; Gene expression; Gene Expression Regulation; Gene regulation; Genes; Genetic aspects; Genetic engineering; Genetic transformation; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - physiology; Kidney diseases; Lens, Crystalline - blood supply; Lens, Crystalline - metabolism; Lenses; Male; Markers; Mesenchyme; Mesoderm - metabolism; Metallothionein; Metallothionein - chemistry; Mice; Mice, Transgenic; Modulation; Morphology; Oligonucleotides; Physiology; Proteins; Proto-oncogenes; rho GTP-Binding Proteins - metabolism; Rodents; Signaling; Transcription; Transcription factors; Transformation; Transgenic animals; Transgenic mice; Vascularization
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0007058

The Dbl family of proteins represents a large group of proto-oncogenes involved in cell growth regulation. The numerous domains that are present in many Dbl family proteins suggest that they act to integrate multiple inputs in complicated signaling networks involving the Rho GTPases. Alterations of the normal function of these proteins lead to pathological processes such as developmental disorders and neoplastic transformation. We generated transgenic mice introducing the cDNA of Dbl oncogene linked to the metallothionein promoter into the germ line of FVB mice and found that onco-Dbl expression in mouse lenses affected proliferation, migration and differentiation of lens epithelial cells. We used high density oligonucleotide microarray to define the transcriptional profile induced by Dbl in the lenses of 2 days, 2 weeks, and 6 weeks old transgenic mice. We observed modulation of genes encoding proteins promoting epithelial-mesenchymal transition (EMT), such as down-regulation of epithelial cell markers and up-regulation of fibroblast markers. Genes encoding proteins involved in the positive regulation of apoptosis were markedly down regulated while anti-apoptotic genes were strongly up-regulated. Finally, several genes encoding proteins involved in the process of angiogenesis were up-regulated. These observations were validated by histological and immunohistochemical examination of the transgenic lenses where vascularization can be readily observed. Onco-Dbl expression in mouse lens correlated with modulation of genes involved in the regulation of EMT, apoptosis and vasculogenesis leading to disruption of the lens architecture, epithelial cell proliferation, and aberrant angiogenesis. We conclude that onco-Dbl has a potentially important, previously unreported, capacity to dramatically alter epithelial cell migration, replication, polarization and differentiation and to induce vascularization of an epithelial tissue.