Glomerulocystic kidney disease in mice with a targeted inactivation of Wwtr1

Abstract

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.bone ͉ cilia ͉ cysts ͉ glomerulus ͉ gene expression

The N-terminal Phosphodegron Targets TAZ/WWTR1 Protein for SCFβ-TrCP-dependent Degradation in Response to Phosphatidylinositol 3-Kinase Inhibition

“…TAZ is involved in the development of multiple organs, such as lung, fat, muscle, bone, limb, and heart, as well as many cellular processes, including stem cell differentiation, cell proliferation, and epithelial mesenchymal transition (EMT) 3 (4, 10 -15). Taz knock-out mice develop two severe abnormalities: polycystic kidney disease and emphysema (16,17).…”

The Hippo Tumor Pathway Promotes TAZ Degradation by Phosphorylating a Phosphodegron and Recruiting the SCFβ-TrCP E3 Ligase

“…The biological functions of the two proteins are not redundant. For example, the Yap knock-out mice are early embryonic lethal while Taz knock-out mice go through normal development but develop cystic renal disease (22,23,35). Furthermore, elevated protein levels of both YAP and TAZ have been found in human cancers, but with clear organ and tissues specificities.…”

“…TAZ is involved in the development of multiple organs such as lung, fat, muscle, bone, limb, and heart as well as many cellular processes including stem cell differentiation, cell proliferation, epithelial mesenchymal transition (EMT) 4 (15)(16)(17)(18)(19)(20)(21). Taz knock-out mice develop two severe abnormalities: polycystic kidney disease and emphysema (22,23).…”

c-Myc Signalling in the Genetic Mechanism of Polycystic Kidney Disease

“…Recently, accumulating evidence has shown that effectors of Wnt and Hippo pathways for example, are often shared and crosstalk through multiple mechanisms (for review (110)). Significantly, targeting several effectors of these pathways led to renal cyst formation in the mouse (111)(112)(113)(114)(115)(116)(117). Similarities between dysregulation of polycystin(s) and c-Myc suggest that these proteins are involved in a network or in common signalling pathways essential in renal development and in the ADPKD adult pathologic condition.…”