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First published online 2 December 2004
doi: 10.1242/dev.01573

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Smad1, ß-catenin and Tcf4 associate in a molecular complex with the Myc promoter in dysplastic renal tissue and cooperate to control Myc transcription

¹ Program in Developmental Biology, Research Institute, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada
² Program in Developmental Biology, Research Institute, The Hospital for Sick Children and Division of Nephrology, Department of Paediatrics, University of Toronto, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada

^* Author for correspondence (e-mail: norman.rosenblum{at}sickkids.ca)

Accepted 3 November 2004

Renal dysplasia, the major cause of childhood renal failure in humans, arises from perturbed renal morphogenesis and molecular signaling during embryogenesis. Recently, we discovered induction of molecular crosstalk between Smad1 and ß-catenin in the TgAlk3^QD mouse model of renal medullary cystic dysplasia. Our finding that Myc, a Smad and ß-catenin transcriptional target and effector of renal epithelial dedifferentiation, is misexpressed in dedifferentiated epithelial tubules provided a basis for investigating coordinate transcriptional control by Smad1 and ß-catenin in disease. Here, we report enhanced interactions between a molecular complex consisting of Smad1, ß-catenin and Tcf4 and adjacent Tcf- and Smad-binding regions located within the Myc promoter in TgAlk3^QD dysplastic renal tissue, and Bmp-dependent cooperative control of Myc transcription by Smad1, ß-catenin and Tcf4. Analysis of nuclear extracts derived from TgAlk3^QD and wild-type renal tissue revealed increased levels of Smad1/ß-catenin molecular complexes, and de novo formation of chromatin-associated Tcf4/Smad1 molecular complexes in TgAlk3^QD tissues. Analysis of a 476 nucleotide segment of the 1490 nucleotide Myc genomic region upstream of the transcription start site demonstrated interactions between Tcf4 and the Smad consensus binding region and associations of Smad1, ß-catenin and Tcf4 with oligo-duplexes that encode the adjacent Tcf- and Smad-binding elements only in TgAlk3^QD tissues. In collecting duct cells that express luciferase under the control of the 1490 nucleotide Myc genomic region, Bmp2-dependent stimulation of Myc transcription was dependent on contributions by each of Tcf4, ß-catenin and Smad1. These results provide novel insights into mechanisms by which interacting signaling pathways control transcription during the genesis of renal dysplasia.

Key words: Smad1, ß-catenin, Tcf4, renal dysplasia, cystogenesis, Myc

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