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Cited1 Is a Bifunctional Transcriptional Cofactor That Regulates Early Nephronic Patterning

Sergey Plisov, Michael Tsang, Genbin Shi^*, Scott Boyle^*, Kiyoshi Yoshino, Sally L. Dunwoodie^,||,¶, Igor B. Dawid, Toshi Shioda^**, Alan O. Perantoni and Mark P. de Caestecker^*

^* Division of Nephrology, Vanderbilt University School of Medicine, Nashville, Tennessee; Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick, Maryland; Laboratory of Molecular Genetics, National Institute of Child Health and Human Development, Bethesda, Maryland; Developmental Biology Program, Victor Chang Cardiac Research Institute, St. Vincent’s Hospital, Darlinghurst, New South Wales, Australia; ^|| Department of Biotechnology and Biomolecular Sciences; ^¶ St. Vincent’s Clinical School, University of New South Wales, Kensington, New South Wales, Australia; and ^** Department of Tumor Biology, Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts

Address correspondence to: Dr. Mark P. de Caestecker, Nephrology Division, Vanderbilt University School of Medicine, S3223 Medical Center, North 21st Street South, Nashville, TN 37232. Phone: 615-343-2844; Fax: 615-343-2675; E-mail: mark.de.caestecker{at}vanderbilt.edu

Received for publication June 15, 2004. Accepted for publication March 7, 2005.

In a screen to identify factors that regulate the conversion of mesenchyme to epithelium during the early stages of nephrogenesis, it was found that the Smad4-interacting transcriptional cofactor, Cited1, is expressed in the condensed cap mesenchyme surrounding the tip of the ureteric bud (UB), is downregulated after differentiation into epithelia, and has the capacity to block UB branching and epithelial morphogenesis in cultured metanephroi. Cited1 represses Wnt/-catenin but activates Smad4-dependent transcription involved in TGF- and Bmp signaling. By modifying these pathways, Cited1 may coordinate cellular differentiation and survival signals that regulate nephronic patterning in the metanephros.

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