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 and 2 mRNA is most abundant in adult kidney while Glis3 is expressed in several tissues. 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. In addition to links between these signaling pathways, Glis proteins interact with the nuclear receptor RORgamma signaling pathway: Glis3 can suppress the transcriptional activation by RORgamma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES100485-03
Application #
7007508
Study Section
(CBG)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2004
Total Cost
Indirect Cost
Name
U.S. National Inst of Environ Hlth Scis
Department
Type
DUNS #
City
State
Country
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
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; 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
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

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