Glomerulocystic kidney disease in mice with a targeted inactivation of Wwtr1

Wwtr1 is a widely expressed 14-3-3-binding protein that regulates the activity of several transcription factors involved in development and disease. To elucidate the physiological role of Wwtr1, we generated Wwtr1-/- mice by homologous recombination. Surprisingly, although Wwtr1 is known to regulate the activity of Cbfa1, a transcription factor important for bone development, Wwtr1-/- mice show only minor skeletal defects. However, Wwtr1-/- animals present with renal cysts that lead to end-stage renal disease. Cysts predominantly originate from the dilation of Bowman's spaces and atrophy of glomerular tufts, reminiscent of glomerulocystic kidney disease in humans. A smaller fraction of cysts is derived from tubules, in particular the collecting duct (CD). The corticomedullary accumulation of cysts also shows similarities with nephronophthisis. Cells lining the cysts carry fewer and shorter cilia and the expression of several genes associated with glomerulocystic kidney disease (Ofd1 and Tsc1) or encoding proteins involved in cilia structure and/or function (Tg737, Kif3a, and Dctn5) is decreased in Wwtr1-/- kidneys. The loss of cilia integrity and the down-regulation of Dctn5, Kif3a, Pkhd1 and Ofd1 mRNA expression can be recapitulated in a renal CD epithelial cell line, mIMCD3, by reducing Wwtr1 protein levels using siRNA. Thus, Wwtr1 is critical for the integrity of renal cilia and its absence in mice leads to the development of renal cysts, indicating that Wwtr1 may represent a candidate gene for polycystic kidney disease in humans.