HNF-6 Is Expressed in Endoderm Derivatives and Nervous System of the Mouse Embryo and Participates to the Cross-Regulatory Network of Liver-Enriched Transcription Factors

Landry, Claire; Clotman, Frédéric; Hioki, Takeshi; Oda, Hiroaki; Picard, Jacques; Lemaigre, Frédéric P.; Rousseau, Guy

doi:10.1006/dbio.1997.8757

Cited by 147 publications

(131 citation statements)

References 42 publications

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“…This is somehow in contrast with the fact that in developing embryos, HNF-6 is expressed in a lineage-restricted manner [17]. However, several lineage-restricted factors, which include HNF-1α, HNF-1β and PDX-1 [29,34,35], are known to be expressed in undifferentiated ES cells and we show here that this is also the case for NGN-3.…”

Section: Discussioncontrasting

confidence: 59%

“…During pancreas development, HNF-6 is expressed in the pre-pancreatic endoderm and in the pluripotent pancreatic epithelium that gives rise to the endocrine islets, to the exocrine acini and to the ducts. It is also weakly expressed in the acinar and ductal cells but not in the differentiated endocrine cells [17,18,19]. Gene knock-out studies in mice have shown that in the absence of HNF-6 the number of endocrine cells at birth is dramatically reduced [19].…”

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confidence: 99%

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HNF-6-independent differentiation of mouse embryonic stem cells into insulin-producing cells

Houard¹,

Rousseau²,

Lemaigre³

2003

Diabetologia

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Aims/hypothesis. Embryonic stem cells, when grown as embryoid bodies, spontaneously generate insulinproducing cells which could be used in therapy of diabetes mellitus, provided that their selection and differentiation are optimized. To achieve such optimization, one needs to know whether the differentiation of cells in embryoid bodies mimicks that of pancreatic beta cells in embryos. To address this question we verified if the differentiation of the insulin-producing cells in embryoid bodies requires Hepatocyte Nuclear Factor-6 (HNF-6), a transcription factor known to control pancreatic endocrine differentiation in embryos. Methods. We generated mouse Hnf6−/− embryonic stem cells and grew them as embryoid bodies. The expression of HNF-6, insulin, and transcription factors that are regulated by HNF-6 in developing pancreas was compared in wild-type and Hnf6−/− embryoid bodies. Results.No difference was observed in the expression of insulin between wild-type and Hnf6−/− embryoid bodies. In both cases insulin was expressed in the outer layer of cells, which is similar to the visceral endoderm. In wild-type embryoid bodies HNF-6 was transiently expressed in the outer layer of cells, but was not co-expressed with insulin. The expression of genes that are targets of HNF-6 in developing pancreas was unaffected in Hnf6−/− embryoid bodies. Conclusion/interpretation. In contrast to the development of pancreatic beta cells, the differentiation of insulin-producing cells in embryoid bodies did not require HNF-6. Thus, the differentiation mechanism of insulin-producing cells in embryoid bodies differs from that of the beta cells and it is likely to resemble that of insulin-producing cells in the visceral endoderm. [Diabetologia (2003) 46:378-385]

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Section: Discussioncontrasting

confidence: 59%

mentioning

confidence: 99%

HNF-6-independent differentiation of mouse embryonic stem cells into insulin-producing cells

Houard¹,

Rousseau²,

Lemaigre³

2003

Diabetologia

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“…14,19 It has been proposed that GH induction of HNF-6 occurs via FoxA2 or HNF-4␣ transcriptional activation of HNF-6, or by GH effect on diminishing the repressive effect of C/EBP␣ on HNF-6 transcription. 20 HNF-6 in turn can transcriptionally regulate HNF-4␣, 21 suggesting the possibility that CYP7A1 transcriptional induction during GH treatment may be directly mediated via HNF-4␣ through GH-mediated increase in hepatic expression of HNF-6. Using wild-type CD1 mice, however, GH has a minimal effect on the expression levels of FoxA2 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Accumulating evidence suggests that maintenance of hepatocyte-specific expression of the HNF-6, HNF-4␣, FoxA2, and C/EBP␣ transcription factors involves cross-regulation by one or more unrelated liver-enriched transcription factors. 9,14,19,21 They have thus been proposed to participate in a complex network of autoregulatory loops to control hepatic gene expression. 20 The fact that we observed no change in hepatic expression of FoxA2, HNF-4␣, or C/EBP␣ following GH administration to wild-type CD1 mice suggests that GH-mediated stimulation of CYP7A1 is likely mediated through increased HNF-6 levels and not through the HNF-4␣ protein.…”

Section: Hnf-6 Foxa1mentioning

confidence: 99%

In vivo regulation of murine CYP7A1 by HNF-6: A novel mechanism for diminished CYP7A1 expression in biliary obstruction

et al. 2004

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Disruption of the enterohepatic bile acid circulation during biliary tract obstruction leads to profound perturbation of the cholesterol and bile acid metabolic pathways. Several families of nuclear receptor proteins have been shown to modulate this critical process by regulating hepatic cholesterol catabolism and bile acid synthesis through the transcriptional control of cholesterol 7-␣ hydroxylase (CYP7A1). Hepatocyte nuclear factor (HNF) 6 (also known as OC-1) is a member of the ONECUT family of transcription factors that activate numerous hepatic target genes essential to liver function. We have previously shown that hepatic expression of mouse HNF-6 messenger RNA (mRNA) and protein significantly decrease following bile duct ligation. Because CYP7A1 contains potential HNF-6 binding sites in its promoter region, we tested the hypothesis that HNF-6 transcriptionally regulates CYP7A1. Following bile duct ligation, we demonstrated that diminished HNF-6 mRNA levels correlate with a reduction in CYP7A1 mRNA expression. Increasing hepatic levels of HNF-6 either by infection with recombinant adenovirus vector expressing HNF-6 cDNA by growth hormone treatment leads to an induction of CYP7A1 mRNA. To directly evaluate if HNF-6 is a transcriptional activator for CYP7A1, we used deletional and mutational analyses of CYP7A1 promoter sequences and defined sequences ؊206/؊194 to be critical for CYP7A1 transcriptional stimulation by HNF-6 in cotransfection assays. In conclusion, the HNF-6 protein is a component of the complex network of hepatic transcription factors that regulates the expression of hepatic genes essential for bile acid homeostasis and cholesterol/lipid metabolism in normal and pathological conditions.

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“…Two members of this class are present in mammalian liver, namely HNF-6 and Onecut-2 (OC-2) [14]. HNF-6 is expressed in the embryonic liver and pancreas [15,16] and it plays an important role in the development of these organs [17]. In the adult, HNF-6 is involved in the liver-specific control of several genes of glucose metabolism, e.g.…”

mentioning

confidence: 99%

Liver glucokinase gene expression is controlled by the onecut transcription factor hepatocyte nuclear factor-6

et al. 2002

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Aims/hypothesis. Glucokinase plays a key role in glucose homeostasis and the expression of its gene is differentially regulated in pancreatic beta cells and in the liver through distinct promoters. The factors that determine the tissue-specific expression of the glucokinase gene are not known. Putative binding sites for hepatocyte nuclear factor (HNF)-6, the prototype of the ONECUT family of transcription factors, are present in the hepatic promoter of the glucokinase gene and in diabetic hnf6 knockout mice. We hypothesized that HNF-6 controls the activity of the hepatic glucokinase promoter. Methods. We tested the binding of recombinant HNF-6 to DNA sequences from the mouse hepatic glucokinase promoter in vitro and the effect of HNF-6 on promoter activity in transfected cells. We investigated in vivo the role of HNF-6 in mice by examining the effect of inactivating the hnf6 gene on glucokinase gene-specific deoxyribonuclease I hypersensitive sites in liver chromatin and on liver glucokinase mRNA concentration.Results. HNF-6 bound to the hepatic promoter of the glucokinase gene and stimulated its activity. Inactivation of the hnf6 gene did not modify the pattern of deoxyribonuclease I hypersensitive sites but was associated with a decrease of liver glucokinase mRNA to half the control value. Conclusions/interpretation. Although HNF-6 is not required to open chromatin of the hepatic promoter of the glucokinase gene, it stimulates transcription of the glucokinase gene in the liver. This could partly explain the diabetes observed in hnf6 knockout mice.

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HNF-6 Is Expressed in Endoderm Derivatives and Nervous System of the Mouse Embryo and Participates to the Cross-Regulatory Network of Liver-Enriched Transcription Factors

Cited by 147 publications

References 42 publications

HNF-6-independent differentiation of mouse embryonic stem cells into insulin-producing cells

HNF-6-independent differentiation of mouse embryonic stem cells into insulin-producing cells

In vivo regulation of murine CYP7A1 by HNF-6: A novel mechanism for diminished CYP7A1 expression in biliary obstruction

Liver glucokinase gene expression is controlled by the onecut transcription factor hepatocyte nuclear factor-6

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