Glis3 Is Associated with Primary Cilia and Wwtr1/TAZ and Implicated in Polycystic Kidney Disease

LRB, Cell Biology Section, Division of Intramural Research, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 04/2009; 29(10):2556-69. DOI: 10.1128/MCB.01620-08
Source: PubMed


In this study, we describe the generation and partial characterization of Krüppel-like zinc finger protein Glis3 mutant (Glis3zf/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 Glis3zf/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.

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    • "Indeed, duct morphogenesis is more largely affected in Hnf1b mutants than in Hnf6 mutants, as cysts affect all types of ducts, and not only intralobular and interlobular ducts, as in Hnf6 mutants (Pierreux et al., 2006). Moreover, whereas Glis3 expression was unaffected in Hnf6-null pancreas (Kang et al., 2009b), we found that Glis3 is downstream Hnf1b, which is particularly interesting as both factors are associated with cystogenesis (Kang et al., 2009a,b) and endocrine cell development (Kim et al., 2012). Taking advantage of Hnf1b ChIP-seq analysis on embryonic kidneys, we identified Glis3 and Cys1 as novel Hnf1b targets in pancreas. "
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    ABSTRACT: Heterozygous mutations in the human HNF1B gene are associated with maturity-onset diabetes of the young type 5 (MODY5) and pancreas hypoplasia. In mouse, Hnf1b heterozygous mutants do not exhibit any phenotype, whereas the homozygous deletion in the entire epiblast leads to pancreas agenesis associated with abnormal gut regionalization. Here, we examine the specific role of Hnf1b during pancreas development, using constitutive and inducible conditional inactivation approaches at key developmental stages. Hnf1b early deletion leads to a reduced pool of pancreatic multipotent progenitor cells (MPCs) due to decreased proliferation and increased apoptosis. Lack of Hnf1b either during the first or the secondary transitions is associated with cystic ducts. Ductal cells exhibit aberrant polarity and decreased expression of several cystic disease genes, some of which we identified as novel Hnf1b targets. Notably, we show that Glis3, a transcription factor involved in duct morphogenesis and endocrine cell development, is downstream Hnf1b. In addition, a loss and abnormal differentiation of acinar cells are observed. Strikingly, inactivation of Hnf1b at different time points results in the absence of Ngn3(+) endocrine precursors throughout embryogenesis. We further show that Hnf1b occupies novel Ngn3 putative regulatory sequences in vivo. Thus, Hnf1b plays a crucial role in the regulatory networks that control pancreatic MPC expansion, acinar cell identity, duct morphogenesis and generation of endocrine precursors. Our results uncover an unappreciated requirement of Hnf1b in endocrine cell specification and suggest a mechanistic explanation of diabetes onset in individuals with MODY5. © 2015. Published by The Company of Biologists Ltd.
    Development 03/2015; 142(5):871. DOI:10.1242/dev.110759 · 6.46 Impact Factor
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    • "Thus, the development of PKD and NPHP due to Glis3 and Glis2 deficiency, respectively, is consistent with an association between Glis signaling pathways and the primary cilium (figure 2). Although a reduction in the percentage of primary cilium-containing cells was observed in renal cysts, Glis3-deficiency does not result in the loss of the primary cilium in renal tubule epithelial cells, implying that Glis3 is not required for ciliogenesis (Hashimoto et al., 2009; Kang et al., 2009a; Kim et al., 2008). The reduction in primary cilium-containing cells is likely a consequence rather than a cause of renal cyst formation. "
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    ABSTRACT: Gli-similar (Glis) 1-3 proteins constitute a subfamily of Krüppel-like zinc-finger proteins that are closely related to members of the Gli family. Glis proteins have been implicated in several pathologies, including cystic kidney disease, diabetes, hypothyroidism, fibrosis, osteoporosis, psoriasis, and cancer. In humans, a mutation in the Glis2 gene has been linked to the development of nephronophthisis (NPHP), a recessive cystic kidney disease, while mutations in Glis3 lead to an extended multisystem phenotype that includes the development of neonatal diabetes, polycystic kidneys, congenital hypothyroidism, and facial dysmorphism. Glis3 has also been identified as a risk locus for type-1 and type-2 diabetes and additional studies have revealed a role for Glis3 in pancreatic endocrine development, β-cell maintenance, and insulin regulation. Similar to Gli1-3, Glis2 and 3 have been reported to localize to the primary cilium. These studies appear to suggest that Glis proteins are part of a primary cilium-associated signaling pathway(s). It has been hypothesized that Glis proteins are activated through posttranslational modifications and subsequently translocate to the nucleus where they regulate transcription by interacting with Glis-binding sites in the promoter regions of target genes. This chapter summarizes the current state of knowledge regarding mechanisms of action of the Glis family of proteins, their physiological functions, as well as their roles in disease.
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    • "Interestingly, knockout of Glis3 also results in PKD in mice and Glis3 can interact with TAZ in a manner dependent on WW domain and PPXY motif [37]. But genes downregulated in Glis3 knockout mice related to PKD [37] are not the same as those in Taz knockout mice, so how the Glis3 and Taz cooperate in developing PKD is not clear. "
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    International Journal of Biochemistry and Molecular Biology 01/2011; 2(3):247-56.
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