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


RESULTS
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.


CONCLUSIONS
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.
Fardin
Paolo
P
Laboratorio di Biologia Molecolare, Istituto G Gaslini, Genova, Italy.
Ognibene
Marzia
M
Vanni
Cristina
C
De Santanna
Amleto
A
Varesio
Luigi
L
Eva
Alessandra
A
D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D004848:Epithelium / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000502:physiology*; D007908:Lens, Crystalline / Q000098:blood supply* / Q000378:metabolism*; D008297:Male; D008648:Mesoderm / Q000378:metabolism*; D008668:Metallothionein / Q000737:chemistry; D051379:Mice; D008822:Mice, Transgenic; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D020662:Guanine Nucleotide Exchange Factors; C512843:Mcf2 protein, mouse; D008668:Metallothionein; D020741:rho GTP-Binding Proteins