A transcription factor regulatory circuit in differentiated pancreatic cells

Boj, Sylvia F.; Párrizas, Marcelina; Maestro, Miguel A.; Ferrer, Jorge

doi:10.1073/pnas.241349398

Cited by 224 publications

(239 citation statements)

References 39 publications

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“…The P2 promoter contains functional binding sites for the MODY transcription factors HNF-1α, HNF-1β and Pdx1/IPF1, and was proposed to serve as a positive cross-regulatory feedback circuit between HNF-1α and HNF-4α in human pancreatic cells [7].…”

Section: Introductionmentioning

confidence: 99%

Effect of common polymorphisms in the HNF4? promoter on susceptibility to type 2 diabetes in the French Caucasian population

et al. 2005

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Aims/hypothesis: The gene encoding HNF-4α, an orphan nuclear receptor playing critical roles in embryogenesis and metabolism by regulating gene expression in pancreatic beta cells, liver, and other tissues, is localised to chromosome 20q13, where linkage to type 2 diabetes has been shown in multiple studies. As two reports have independently demonstrated a convincing association with variants adjacent to the HNF-4α P2 promoter in Finnish and Ashkenazi Jewish populations, we evaluated their contribution to diabetes risk in the French Caucasian population. Methods: Genotypes for four haplotype tag SNPs were analysed for association with diabetes in a casecontrol study of 744 unrelated type 2 diabetic patients and 686 normoglycaemic subjects, and for linkage in 148 diabetic families in whom significant linkage to the HNF4α region had been shown. Results: The association seen in the Finnish and Ashkenazi studies for SNPs rs2144908 and rs1884614 located within a haplotype block encompassing the beta cell promoter P2 of HNF-4α was not replicated in our study; in French Caucasians the minor allele prevalence was increased in control subjects [odds ratio (OR) 0.80, uncorrected p=0.022 for rs2144908; OR 0.82 uncorrected p=0.058 for rs1884614]. Furthermore, none of the SNPs tested in the French familial sample was associated with diabetes, nor do they appear to contribute to the linkage. Conclusions/interpretation: None of the previously associated SNPs confer an increased risk for diabetes in French Caucasians. A large meta-analysis of association studies will determine whether there is a consistent association between particular SNPs upstream of HNF-4α and type 2 diabetes in several ethnic groups.

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Section: Introductionmentioning

confidence: 99%

Effect of common polymorphisms in the HNF4? promoter on susceptibility to type 2 diabetes in the French Caucasian population

et al. 2005

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“…In ␤-cells, HNF-3␤ and HNF-1␣ may directly regulate PDX-1 gene transcription (10)(11)(12)(13)(14)(15). In addition, HNF-1␣ and HNF-4␣ autoregulate each other's expression (14,16). Interestingly, in contrast to humans, only heterozygous Pdx-1 mutants but not Hnf-4␣, Hnf-1␣, Hnf-1␤, or Beta2 induce a diabetic phenotype in mice, presumably because of the direct importance of Pdx-1 in regulating glucose transporter 2 (Glut-2), glucokinase (Gck), and insulin gene expression.…”

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confidence: 99%

Profound defects in pancreatic β-cell function in mice with combined heterozygous mutations in Pdx-1 , Hnf-1 α, and Hnf-3 β

Shih

Heimesaat

Kuwajima

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Defects in pancreatic ␤-cell function contribute to the development of type 2 diabetes, a polygenic disease that is characterized by insulin resistance and compromised insulin secretion. Hepatocyte nuclear factors (HNFs) -1␣, -3␤, -4␣, and Pdx-1 contribute in the complex transcriptional circuits within the pancreas that are involved in ␤-cell development and function. In mice, a heterozygous mutation in Pdx-1 alone, but not Hnf-1␣ ؉/؊ , Hnf-3␤ ؉/؊ , or Hnf-4␣ ؉/؊ , causes impaired glucose-stimulated insulin secretion in mice. To investigate the possible functional relationships between these transcription factors on ␤-cell activity in vivo, we generated mice with the following combined heterozygous mutations: Pdx-, and Hnf-3␤ ؉/؊ ͞Hnf-4␣ ؉/؊ . The greatest loss in function was in combined heterozygous null alleles of Pdx-1 and Hnf-1␣ (Pdx-1 ؉/؊ ͞Hnf-1␣ ؉/؊ ), or Pdx-1 and Hnf-3␤ (Pdx-1 ؉/؊ ͞Hnf-3␤ ؉/؊ ). Both double mutants develop progressively impaired glucose tolerance and acquire a compromised first-and second-phase insulin secretion profile in response to glucose compared with Pdx-1 ؉/؊ mice alone. The loss in ␤-cell function in Pdx-1 ؉/؊ ͞Hnf-3␤ ؉/؊ mice was associated with decreased expression of Nkx-6.1, glucokinase (Gck), aldolase B (aldo-B), and insulin, whereas Nkx2.2, Nkx-6.1, Glut-2, Gck, aldo-B, the liver isoform of pyruvate kinase, and insulin expression was reduced in Pdx-1 ؉/؊ ͞Hnf-1␣ ؉/؊ mice. The islet cell architecture was also abnormal in Pdx-1 ؉/؊ ͞Hnf-3␤ ؉/؊ and Pdx-1 ؉/؊ ͞Hnf-1␣ ؉/؊ mice, with glucagon-expressing cells scattered throughout the islet, a defect that may be connected to decreased E-cadherin expression. Our data suggest that functional interactions between key islet regulatory factors play an important role in maintaining islet architecture and ␤-cell function. These studies also established polygenic mouse models for investigating the mechanisms contributing to ␤-cell dysfunction in diabetes.hepatocyte nuclear factors ͉ diabetes mellitus ͉ insulin secretion ͉ pancreatic islets G enetic and biochemical studies in humans and mice have identified many key transcription factors that are involved in controlling pancreas development and ␤Ϫcell function in the adult islet (see ref. 1 for review). These factors have in common an islet-enriched expression pattern during pancreatic development, although each [e.g., hepatocyte nuclear factors (HNFs)] are also expressed in extrapancreatic tissues (e.g., intestine, liver, brain͞neurons, and kidney). Heterozygous mutations in a subset of these genes, including HNF-4␣, HNF-1␣, PDX-1, HNF-1␤, and BETA2, are specifically associated with a form of type 2 diabetes, termed maturity-onset diabetes of the young (MODY), that is characterized by an early disease onset (usually Ͻ25 years), autosomal dominant inheritance, and a primary defect in insulin secretion (see ref. 2 for review). There is increasing evidence that these and other islet-enriched transcription factors (e.g., Nkx2.2, Nkx6

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“…It is not clear whether PDX-1 directly regulates the expression of the HNF-1α gene transcription; therefore the regulation of HNF-1α by other transcription factors should be examined. Recent studies have suggested that HNF-1α regulation in the pancreas is more complex rather than a simple linear hierarchy [47,48].…”

Section: Discussionmentioning

confidence: 99%

Expression profile of MODY3/HNF-1α protein in the developing mouse pancreas

et al. 2002

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Aims/hypothesis. One subtype of MODY (MODY3) results from the heterozygous mutation of a hepatocyte nuclear factor (HNF)-1α. The pattern of HNF-1α expression in the normal pancreas has not been determined. This study aimed to clarify the profile of HNF-1α protein expression in the developing mouse pancreas. Methods. Double immunofluorescence staining was carried out for HNF-1α and pancreatic hormones or transcription factors (PDX-1, Pax6, Isl1, and Nkx2.2). The expression of these transcription factors was also studied in the beta cells of HNF-1α mutant mice. Results. HNF-1α was expressed by both endocrine and exocrine cells of the pancreas. Double immunofluorescence staining showed that HNF-1α was expressed in the nuclei of alpha cells, beta cells, delta cells, and pancreatic polypeptide (PP) cells. HNF-1α was first detected in most pancreatic epithelial cells on embryonic day 10.5 (E10.5), and hormone-positive endocrine cells and amylase-positive cells expressed HNF-1α on E15.5. Most of the Pax6-, Isl1-, or PDX-1-positive cells showed co-expression of HNF-1α. However, HNF-1α immunoreactivity was not observed in 36.0% of Nkx2.2-positive cells. Expression of Nkx2.2, Isl1 and Pax6 seemed to be normal in the beta cells of transgenic mice with dominant negative overexpression of HNF-1α. Expression of PDX-1 did not change in the beta cells of pre-diabetic HNF-1α (-/-) mice, but expression was markedly decreased in the diabetic stage. Conclusion/interpretation. HNF-1α is expressed by both endocrine cells and exocrine cells of the pancreas from the foetal stage along with other transcription factors, so HNF-1α might play a role during development. [Diabetologia (2002[Diabetologia ( ) 45:1142[Diabetologia ( -1153

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A transcription factor regulatory circuit in differentiated pancreatic cells

Cited by 224 publications

References 39 publications

Effect of common polymorphisms in the HNF4? promoter on susceptibility to type 2 diabetes in the French Caucasian population

Effect of common polymorphisms in the HNF4? promoter on susceptibility to type 2 diabetes in the French Caucasian population

Profound defects in pancreatic β-cell function in mice with combined heterozygous mutations in Pdx-1 , Hnf-1 α, and Hnf-3 β

Expression profile of MODY3/HNF-1α protein in the developing mouse pancreas

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