In this study, we describe the generation and partial characterization of 
Krüppel-like zinc finger protein Glis3 mutant (Glis3(zf/zf)) mice. These mice 
display abnormalities very similar to those of patients with neonatal diabetes 
and hypothyroidism syndrome, including the development of diabetes and 
polycystic kidney disease. We demonstrate that Glis3 localizes to the primary 
cilium, suggesting that Glis3 is part of a cilium-associated signaling pathway. 
Although Glis3(zf/zf) mice form normal primary cilia, renal cysts contain 
relatively fewer cells with a primary cilium. We further show that Glis3 
interacts with the transcriptional modulator Wwtr1/TAZ, which itself has been 
implicated in glomerulocystic kidney disease. Wwtr1 recognizes a P/LPXY motif in 
the C terminus of Glis3 and enhances Glis3-mediated transcriptional activation, 
indicating that Wwtr1 functions as a coactivator of Glis3. Mutations in the 
P/LPXY motif abrogate the interaction with Wwtr1 and the transcriptional 
activity of Glis3, indicating that this motif is part of the transcription 
activation domain of Glis3. Our study demonstrates that dysfunction of Glis3 
leads to the development of cystic renal disease, suggesting that Glis3 plays a 
critical role in maintaining normal renal functions. We propose that 
localization to the primary cilium and interaction with Wwtr1 are key elements 
of the Glis3 signaling pathway.