Glis1-3 are novel genes recently identified in our laboratory. The Glis1-3 genes encode Kruppel-like zinc finger proteins containing five tandem zinc finger motifs that exhibit highest homology with those of members of the Gli and Zic subfamilies of Kruppel-like proteins. In addition, the zinc finger domain of Glis1 and -3 exhibit high homology with that of Drosophila gleeful/lame duck suggesting that it may be the Drosophila homologue of Glis1 and -3. Northern blot analysis showed that expression of the Glis1-3 mRNAs are most abundant in adult kidney. Whole mount in situ hybridization on mouse embryos demonstrated that Glis1-3 are expressed in a temporal and spatial manner during development. Glis1 expression was most prominent in several defined structures of mesodermal lineage, including craniofacial regions, branchial arches, somites, vibrissal and hair follicles, limb buds, and myotomes suggesting a role at different stages of development. Glis2 was expressed in kidney and neural tube suggesting a role in neurogenesis and kidney development.Glis3 is expressed in specific regions in developing kidney and testis and in a highly dynamic pattern during neurulation. From E11.5 through E12.5 Glis3 was strongly expressed in the interdigital regions, which are fated to undergo apoptosis. The temporal and spatial pattern of Glis1-3 expression observed during embryonic development suggests that they may play a critical role in the regulation of a variety of cellular processes during development. Confocal microscopic analysis showed that Glis1-3 are localized to the nucleus. The punctated pattern suggests that they are part of a larger nuclear protein complex. The zinc finger region in Glis plays an important role in the nuclear localization of these proteins. Electrophoretic mobility shift assays demonstrated that Glis1-3 are able to bind oligonucleotides containing the Gli-binding site consensus sequence GACCACCCAC. Although monohybrid analysis showed that in several cell types Glis1-3 are unable to induce transcription of a reporter, deletion mutant analysis revealed the presence of a strong activation and repressor functions suggesting that these proteins can function as repressors and activators of transcription. Glis3 was found to interact with GLi1 suggesting interaction between the Glis and Gli signaling pathways. Our results suggest that Glis1-3 may play a critical role in the control of gene expression during specific stages of embryonic development. Our hypothesis is that these proteins may act up- and/or downstream of sonic hedgehog, Wnt, BMP, or FGF signaling pathways. ? To obtain insight into the physiological functions of Glis2, mice deficient in Glis2 expression were generated. Glis2 mutant (Glis2mut) mice appear initially healthy but exhibit a significantly shorter lifespan than littermate WT mice due to the development of progressive chronic kidney disease. Histopathological analysis revealed a number of changes in the renal cortex of adult Glis2mut mice. These included tubular atrophy and basement membrane thickening affecting the proximal convoluted tubules and glomeruli. This was accompanied by infiltration of mononuclear (lymphocytic) inflammatory cells and interstitial/glomerular fibrosis. The severity of the fibrosis, inflammatory infiltrates, and the glomerular and tubular changes progressed with age and correlated with increases in blood urea nitrogen and creatinine, the development of proteinuria and increased water consumption and urine output. Ultimately Glis2mut mice die prematurely of renal failure. Comparison of the gene expression profiles of kidneys from 25 and 60 day old WT and Glis2mut mice by microarray analysis showed that a large number of genes involved in immune responses/inflammation and fibrosis/tissue remodeling are induced in kidneys of Glis2 mutant mice, and included several cytokines, adhesion and extracellular matrix proteins. Our data demonstrate that deficiency in Glis2 expression leads to tubular atrophy and progressive fibrosis that ultimately results in renal failure. Our study indicates that Glis2 plays a critical role in the maintenance of normal kidney functions.? Glis3: Glis3 plays a critical role in pancreatic development and has been implicated in a syndrome with neonatal diabetes and hypothyroidism (NDH). We examined three steps critical in the mechanism of the transcriptional regulation by Glis3: its translocation to the nucleus, DNA binding, and transcriptional activity. We demonstrate that the putative bipartite nuclear localization signal is not required, but the tetrahedral configuration of the fourth zinc finger is essential for the nuclear localization of Glis3. We identify (G/C)TGGGGGGT(A/C) as the consensus sequence of the optimal, high affinity Glis3 DNA-binding site (Glis-BS). All five zinc finger motifs are critical for efficient binding of Glis3 to Glis-BS. We show that Glis3 functions as a potent inducer of (Glis-BS)-dependent transcription and contains a transactivation function at its C-terminus. A mutation in Glis3 observed in NDH1 patients results in a frameshift mutation and a C-terminal truncated Glis3. We demonstrate that this truncation does not effect the nuclear localization but results in the loss of Glis3 transactivating activity. The loss in Glis3 transactivating function may be responsible for the abnormalities observed in NDH1. ? To study the physiological function of Glis3, mice deficient in the expression of Glis3 were generated. These mice develop diabetes and polycystic kidney disease. These mice are being characterized.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Intramural Research (Z01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
United States
Zip Code
Jetten, Anton M (2018) GLIS1-3 transcription factors: critical roles in the regulation of multiple physiological processes and diseases. Cell Mol Life Sci 75:3473-3494
Kang, Hong Soon; Kumar, Dhirendra; Liao, Grace et al. (2017) GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation. J Clin Invest 127:4326-4337
Scoville, David W; Kang, Hong Soon; Jetten, Anton M (2017) GLIS1-3: emerging roles in reprogramming, stem and progenitor cell differentiation and maintenance. Stem Cell Investig 4:80
Kang, Hong Soon; Chen, Liang-Yu; Lichti-Kaiser, Kristin et al. (2016) Transcription Factor GLIS3: A New and Critical Regulator of Postnatal Stages of Mouse Spermatogenesis. Stem Cells 34:2772-2783
Scoville, David W; Jetten, Anton M (2016) Studying pancreas development and diabetes using human pluripotent stem cells. Stem Cell Investig 3:80
Slominski, Andrzej T; Zmijewski, Michal A; Jetten, Anton M (2016) ROR? is not a receptor for melatonin (response to DOI 10.1002/bies.201600018). Bioessays 38:1193-1194
Kang, Hong Soon; Takeda, Yukimasa; Jeon, Kilsoo et al. (2016) The Spatiotemporal Pattern of Glis3 Expression Indicates a Regulatory Function in Bipotent and Endocrine Progenitors during Early Pancreatic Development and in Beta, PP and Ductal Cells. PLoS One 11:e0157138
Xie, Luke; Qi, Yi; Subashi, Ergys et al. (2015) 4D MRI of polycystic kidneys from rapamycin-treated Glis3-deficient mice. NMR Biomed 28:546-54
Kojima, Hiroyuki; Takeda, Yukimasa; Muromoto, Ryuta et al. (2015) Isoflavones enhance interleukin-17 gene expression via retinoic acid receptor-related orphan receptors ? and ?. Toxicology 329:32-9
ZeRuth, Gary T; Williams, Jason G; Cole, Yasemin C et al. (2015) HECT E3 Ubiquitin Ligase Itch Functions as a Novel Negative Regulator of Gli-Similar 3 (Glis3) Transcriptional Activity. PLoS One 10:e0131303

Showing the most recent 10 out of 26 publications