HNF-1β regulates transcription of the PKD modifier gene Kif12

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Journal of the American Society of Nephrology (Impact Factor: 9.34). 12/2008; 20(1):41-7. DOI: 10.1681/ASN.2008020238
Source: PubMed


Hepatocyte nuclear factor-1beta (HNF-1beta) is a transcription factor that regulates gene expression in the kidney, liver, pancreas, and other epithelial organs. Mutations of HNF-1beta lead to a syndrome of inherited renal cysts and diabetes and are also a common cause of sporadic renal dysplasia. The full complement of target genes responsible for the functions of HNF-1beta, however, is incompletely defined. Using a functional genomics approach involving chromatin immunoprecipitation and promoter arrays, combined with gene expression profiling, we found that an HNF-1beta target gene in the kidney is kinesin family member 12 (Kif12), a gene previously identified as a candidate modifier gene in the cpk mouse model of polycystic kidney disease. Mutations of HNF-1beta inhibited Kif12 transcription in both cultured cells and knockout mice by altering co-factor recruitment and histone modification. Because kinesin-12 family members participate in orienting cell division, downregulation of Kif12 may underlie the abnormal planar cell polarity observed in cystic kidney diseases.

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    • "Cys1 is responsible for congenital polycystic kidney (CPK) disease (Tao et al., 2009) and is involved in ciliogenesis and polarization of cholangiocytes (Raynaud et al., 2011), whereas Glis3 is implicated in polycystic disease in both kidney (Kang et al., 2009a) and pancreas (Kang et al., 2009b). Among these genes, Kif12, Pkhd1, Pkd2 and Bicc1 were identified as direct Hnf1b targets in the kidney (Gong et al., 2009; Gresh et al., 2004; Verdeguer et al., 2010). Thus, we analyzed whether Hnf1b could be a major regulator of these genes in the pancreas by ChIP experiments on E12.5 pancreata (Fig. 5V). "
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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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    • "Additionally, it has been reported that the pathologic conditions in a polycystic kidney disease mouse model may be caused by the inhibition of KIF12 transcription resulting from a mutation in HNF-1beta, a regulator of Kif12 expression (Gong et al., 2009). Moreover, numerous studies have suggested a relationship between disorders in kinesin expression and tumorigenesis (Yu and Feng, 2010). "
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