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The Wilms Tumor Suppressor Wt1 Promotes Cell Adhesion through Transcriptional Activation of the α4integrin Gene*

Cell-matrix interaction through specific adhesion molecules is a critical step during organ development. In addition, down-regulation of cell adhesion receptors may promote tumor invasion and metastasis. We show here that the Wilms tumor suppressor Wt1, which is necessary for normal development of the epicardium, coronary vessels, genitourinary system, and other tissues, activates transcription of the α4integrin gene. Binding of the Wt1(-KTS) form, which is transcriptionally active, to the proximal α4integrin promoter was demonstrated by electrophoretic mobility shift assay and chromatin immunoprecipitation. A reporter construct harboring ∼1.9 kb of the human α4integrin gene promoter was activated significantly by transient co-transfection of a Wt1(-KTS) expression plasmid. Introducing mutations in two identified Wt1(-KTS) binding motifs in the proximal promoter of the α4integrin gene abrogated this stimulatory effect. Endogenous α4integrin transcripts were increased more than 3-fold in human embryonic kidney 293 cells with stable expression of the Wt1(-KTS) protein. Wt1-overexpressing cells showed augmented adhesion to the α4integrin ligand vascular cell adhesion molecule-1 that was abolished upon incubation with an inhibitory α4integrin antibody. Double immunofluorescent staining revealed co-localization of Wt1 and α4integrin in the developing epicardium of mouse embryos. Cardiac expression of α4integrin was reduced significantly in embryos with a homozygous Wt1 defect (Wt1-/-). These findings demonstrate that Wt1 can support cell adhesion through enhanced expression of α4integrin. This transcriptional activation of the α4integrin gene by Wt1(-KTS) might contribute to normal formation of the epicardium and other tissues in the developing embryo.