To obtain insight into the physiological functions of the Krüppel-like zinc finger protein Gli-similar 2 (Glis2), mice deficient in Glis2 expression were generated. Glis2 mutant (Glis2(mut)) mice exhibit significantly shorter life spans than do littermate wild-type (WT) mice due to the development of progressive chronic kidney disease with features resembling nephronophthisis. Glis2(mut) mice develop severe renal atrophy involving increased cell death and basement membrane thickening in the proximal convoluted tubules. This development is accompanied by infiltration of lymphocytic inflammatory cells and interstitial/glomerular fibrosis. The severity of the fibrosis, inflammatory infiltrates, and glomerular and tubular changes progresses with age. Blood urea nitrogen and creatinine increase, and Glis2(mut) mice develop proteinuria and ultimately die prematurely of renal failure. A comparison of the gene expression profiles of kidneys from 25-day-old/60-day-old WT and Glis2(mut) mice by microarray analysis showed increased expressions of many genes involved in immune responses/inflammation and fibrosis/tissue remodeling in kidneys of Glis2(mut) mice, including several cytokines and adhesion and extracellular matrix proteins. Our data demonstrate that a deficiency in Glis2 expression leads to tubular atrophy and progressive fibrosis, similar to nephronophthisis, that ultimately results in renal failure. Our study indicates that Glis2 plays a critical role in the maintenance of normal kidney architecture and functions.

The Krüppel-like zinc finger transcription factor, Glis3, has been associated with neonatal diabetes in humans and mice, and implicated in the regulation of pancreatic β-cell generation. However, its precise function in the development of pancreatic β-cells has not yet been elucidated. In this study, we provide evidence that Glis3 regulates Neurogenin 3 (Ngn3) through its distal promoter region. Previous studies showed that the distal region and proximal region of Ngn3 promoter contains various transcription binding sites, including binding sites for pancreatic and duodenal homeobox 1 (Pdx1), Hnf1β and Hnf6. Interestingly, putative Glis3 binding sites (Glis3BS) were found in the distal region of Ngn3 promoter close to the Hnf6 binding sites. This suggested that along with Hnf6, Glis3 may also be involved in the regulation of Ngn3 expression. This hypothesis is supported by data showing that Glis3 can bind to the Ngn3 promoter directly and activate Ngn3 transcriptional activity. Additionally, Glis3 can interact directly with Hnf6 in vitro and in vivo. The amino-terminus in Glis3 and the homeodomain of Hnf6 are critical for this interaction. These data suggest that crosstalk between Glis3 and Hnf6 may play an important role in the regulation of Ngn3 during pancreatic endocrine progenitor cell specification and development.