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Vol. 16, Issue 9, 4398-4409, September 2005

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Inhibition of Pkhd1 Impairs Tubulomorphogenesis of Cultured IMCD Cells

Weiyi Mai ^* , Dong Chen ^*, Tianbing Ding ^*, Ingyu Kim ^*, Sujun Park ^*, Sae-youll Cho ^*, Julia S.F. Chu , Dan Liang ^*, Ning Wang ^*, Dianqing Wu , Song Li , Ping Zhao ^||, Roy Zent ^* ¶ #, and Guanqing Wu ^* || @

^* Department of Medicine, Vanderbilt University, Nashville, TN 37232; ^@ Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232; ^¶ Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232; Department of Genetics and Developmental Biology, University of Connecticut, Farmington, CT 06030; Department of Bioengineering, University of California-Berkeley, Berkeley, CA 94720; ^|| Laboratory of Translational Cancer Research, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing 100021, China; ^# Department of Research Medicine, Veterans Administration Hospital, Nashville, TN 37232; and Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China

Submitted November 22, 2004; Revised May 16, 2005; Accepted June 15, 2005
Monitoring Editor: Keith Mostov

Fibrocystin/polyductin (FPC), the gene product of PKHD1, is responsible for autosomal recessive polycystic kidney disease (ARPKD). This disease is characterized by symmetrically large kidneys with ectasia of collecting ducts. In the kidney, FPC predominantly localizes to the apical domain of tubule cells, where it associates with the basal bodies/primary cilia; however, the functional role of this protein is still unknown. In this study, we established stable IMCD (mouse inner medullary collecting duct) cell lines, in which FPC was silenced by short hairpin RNA inhibition (shRNA). We showed that inhibition of FPC disrupted tubulomorphogenesis of IMCD cells grown in three-dimensional cultures. Pkhd1-silenced cells developed abnormalities in cell-cell contact, actin cytoskeleton organization, cell-ECM interactions, cell proliferation, and apoptosis, which may be mediated by dysregulation of extracellular-regulated kinase (ERK) and focal adhesion kinase (FAK) signaling. These alterations in cell function in vitro may explain the characteristics of ARPKD phenotypes in vivo.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Guanqing Wu (guanqing.wu{at}vanderbilt.edu).

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