Identification of connective tissue growth factor as a target of WT1 transcriptional regulation

The Wilms tumor suppressor WT1 has transcription-activating and -suppressin g capabilities. WT1-responsive promoters have been described; however, in l arge part, it remains unclear which potential downstream genes are physiolo gically relevant and mediate the function of WT1 in tumorigenesis and devel opment. To identify genes regulated by WT1 in vivo, we used a dominant-nega tive version of WT1 to modulate WT1 activity in a Wilms tumor cell line. Sc reening oligonucleotide arrays with RNA from these cells uncovered a number of genes whose expression was altered by abrogation of WT1 function. Sever al of the genes encode members of the CCN family of growth regulators. The promoter of one of these genes, connective tissue growth factor (CTGF), is suppressed by WT1 both in its endogenous location and in reporter construct s. WT1 regulation of CTGF expression is not mediated by previously identifi ed WT1 recognition elements and may therefore involve a novel mechanism. Ou r results indicate that CTGF is a bona fide target of WT1 transcriptional s uppression and likely plays a role in Wilms tumorigenesis and associated di sease syndromes.