Regulation of a Transcription Factor Network Required for Differentiation and Metabolism

Duncan, Stephen A.; Navas, María-Ángeles; Dufort, Daniel; Rossant, Janet; Stoffel, Markus

doi:10.1126/science.281.5377.692

Cited by 321 publications

(259 citation statements)

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“…This is due either to functional redundancy between individual FoxA and GATA factor proteins or an essential role for some of these factors prior to the onset of hepatic development. [61][62][63][64][65][66][67][68][69][70] For example, development of Gata6 Ϫ/Ϫ mouse embryos is blocked before hepatic specification due to an indispensable requirement for GATA6 in extraembryonic endoderm differentiation. 63,65 This early embryonic lethality has, however, recently been circumvented by providing Gata6 Ϫ/Ϫ embryos with a wild-type extra-embryonic endoderm via tetraploid embryo complementation.…”

Section: From Where Do Hepatic Cells Arise?mentioning

confidence: 99%

Embryonic development of the liver

2005

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Section: From Where Do Hepatic Cells Arise?mentioning

confidence: 99%

Embryonic development of the liver

2005

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“…Of these, HNF-3b has been shown to be involved in beta-cell-specific transcription of the IPF1 gene [7]. Characterization of HNF-3b zero embryonic stem cells has suggested that HNF-3b positively regulates the HNF-4a/HNF-1a genes and their downstream target genes [8]. Thus, the molecular defects of HNF-3b or accessory factors in the functional complex could cause a decrease in synthesis of IPF1 and HNF-4a/ HNF-1a.…”

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confidence: 99%

Cloning of cDNA and the gene encoding human hepatocyte nuclear factor (HNF)-3β and mutation screening in Japanese subjects with maturity-onset diabetes of the young

et al. 2000

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Maturity-onset diabetes of the young (MODY) is an autosomal dominant form of early-onset Type II (non±insulin±dependent) diabetes mellitus. Five different forms of MODY have been identified [1]. Hepatocyte nuclear factor (HNF)-1a/MODY3, a homeodomain-containing transcription factor, functions as a homodimer or a heterodimer with structurally related HNF-1b/MODY5. Hepatocyte nuclear factor-4a/MODY1, a member of the nuclear receptor superfamily, is a positive regulator of HNF-1a gene transcription. Insulin promoter factor-1 (IPF1)/ MODY4, which is required for pancreatic development and insulin gene transcription, regulates the expression of the gene encoding glucokinase/MODY2. Recently, characterization of HNF-1a-knockout mice and insulinoma cells overexpressing HNF-1a and its dominant-negative mutant indicated that HNF-1a is essential for insulin gene transcription and beta-cell glycolytic signalling [2,3]. The functional relation of proteins encoded by these MODY genes suggests the importance of the HNF-transcription cascade in determining beta-cell function. Diabetologia (2000) 43: 121±124 Short communicationCloning of cDNA and the gene encoding human hepatocyte nuclear factor (HNF)-3b and mutation screening in Japanese subjects with maturity-onset diabetes of the young Abstract Aims/hypothesis. Molecular defects of the genes for transcription factors, hepatocyte nuclear factor (HNF)-4a, HNF-1a, HNF-1b and insulin promoter factor-1 cause maturity-onset diabetes of the young (MODY1, 3, 5, and 4, respectively). This suggests the HNF-related transcription cascade is important in insulin secretion which is induced by glucose. These genes and the gene encoding glycolytic enzyme glucokinase (MODY2) are, however, responsible for only 15±20 % of cases of MODY in the Japanese. Searching for a novel form of MODY in this population, we cloned a new candidate gene encoding human HNF-3b, a winged helix transcription factor, which also belongs to the same HNF-transcription cascade. Methods. The cDNA clone for human HNF-3b was isolated from a liver cDNA library. The gene was also cloned from a genomic library and its organization and chromosomal localization were determined. We screened 68 Japanese subjects with MODY/early-onset diabetes for mutations in this gene. Results. Human HNF-3b is composed of 457 amino acids. The human gene, which was mapped to the segment 30 cR from SHGC-37 039 on chromosome 20 p by radiation hybrid mapping, spans approximately 4.5 kb and consists of three exons. Direct sequencing of the exons and flanking regions identified one missense mutation A328 V and seven polymorphisms, although the functional significance of the mutation in the pathogenesis of diabetes is not known. Conclusion/interpretation. The characterization of the structure of the HNF-3b gene and its mapping in the framework of markers will be helpful in genetic studies of the various forms of diabetes mellitus. [Diabetologia (2000) Corresponding author: J. Takeda, MD Laboratory of Molecular Genetics, Department of Cell Biology, I...

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“…Indeed, in animals, the visceral endoderm produces a number of proteins such as, for instance, alpha foetoprotein, transthyretin, apolipoproteins and glucose transporters which are also found in the outer cell layer of the EBs [27]. In addition, tissuespecific transcriptional regulators of these genes in the visceral endoderm are functional in the outer layer of EBs [28,29]. Insulin is also expressed in the yolk sac visceral endoderm [30], which is consistent with our present observation that insulin is produced by the outer cell layer of EBs.…”

Section: Discussionmentioning

confidence: 99%

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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Regulation of a Transcription Factor Network Required for Differentiation and Metabolism

Cited by 321 publications

References 24 publications

Embryonic development of the liver

Embryonic development of the liver

Cloning of cDNA and the gene encoding human hepatocyte nuclear factor (HNF)-3β and mutation screening in Japanese subjects with maturity-onset diabetes of the young

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

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