Distinct Roles of HNF1 Β , HNF1 α , and HNF4 α in Regulating Pancreas Development, Β -Cell Function and Growth

Maestro, Miguel A.; Cardalda, Carina; Boj, Sylvia F.; Luco, Reini F.; Servitja, Joan Marc; Ferrer, Jorge

doi:10.1159/000109603

Cited by 106 publications

(92 citation statements)

References 67 publications

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“…We have subsequently confirmed visfatin regulation of mRNA expression of several of these genes using a separate real-time PCR using prevalidated primers (Supplementary Figure). Previously published reports have highlighted the importance of these genes in b-cell function, particularly hepatocyte nuclear factor (HNF)4a and HNF1b (Maestro et al 2007), two genes which form single gene defects in forms of maturity onset diabetes of the young (MODY1 and MODY5 respectively). The marked up-regulation of these important transcription factors fits well with the observation here that visfatin causes an increase in insulin secretion (Fig.…”

Section: Discussionmentioning

confidence: 99%

Visfatin regulates insulin secretion, insulin receptor signalling and mRNA expression of diabetes-related genes in mouse pancreatic β-cells

Brown¹,

Onyango²,

Ramanjaneya³

et al. 2009

Journal of Molecular Endocrinology

102

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The role of the adipocyte-derived factor visfatin in metabolism remains controversial, although some pancreatic b-cellspecific effects have been reported. This study investigated the effects of visfatin upon insulin secretion, insulin receptor activation and mRNA expression of key diabetes-related genes in clonal mouse pancreatic b-cells. b-TC6 cells were cultured in RPMI 1640 and were subsequently treated with recombinant visfatin. One-hour static insulin secretion was measured by ELISA. Phospho-specific ELISA and western blotting were used to detect insulin receptor activation. Real-time SYBR Green PCR array technology was used to measure the expression of 84 diabetes-related genes in both treatment and control cells. Incubation with visfatin caused significant changes in the mRNA expression of several key diabetes-related genes, including marked up-regulation of insulin (9-fold increase), hepatocyte nuclear factor (HNF)1b (32-fold increase), HNF4a (16-fold increase) and nuclear factor kB (40-fold increase). Significant down-regulation was seen in angiotensin-converting enzyme (K3 . 73-fold) and UCP2 (K1 . 3-fold). Visfatin also caused a significant 46% increase in insulin secretion compared to control (P!0 . 003) at low glucose, and this increase was blocked by co-incubation with the specific nicotinamide phosphoribosyltransferase inhibitor FK866. Both visfatin and nicotinamide mononucleotide induced activation of both insulin receptor and extracellular signal-regulated kinase (ERK)1/2, with visfatin-induced insulin receptor/ERK1/2 activation being inhibited by FK866. We conclude that visfatin can significantly regulate insulin secretion, insulin receptor phosphorylation and intracellular signalling and the expression of a number of b-cell function-associated genes in mouse b-cells.

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Section: Discussionmentioning

confidence: 99%

Visfatin regulates insulin secretion, insulin receptor signalling and mRNA expression of diabetes-related genes in mouse pancreatic β-cells

Brown¹,

Onyango²,

Ramanjaneya³

et al. 2009

Journal of Molecular Endocrinology

102

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“…In Pdx1 null mice the pancreatic buds form, but further development of the pancreas fails at about E10.5 (Jonsson et al 1994;Offield et al 1996), while in humans with homozygous mutations in Pdx1 (the human gene is called Ipf1) the pancreas also fails to form (Stoffers et al 1997) . Members of the hepatocyte nuclear factor family (Hnfβ, Hnf1β, and Hnf6) have also been shown to delineate regions of the foregut endoderm from which the pancreas forms, and inactivation of any of these genes leads to abnormalities in the endoderm and pancreas (Maestro et al 2007). Hnf1β (Tcf2) has been specifically implicated in bud formation as shown by the early rescued null mutants for this gene (null mutants die before gastrulation), which only form a dorsal bud rudiment that transiently expresses the transcription factors Pdx1 and the homeodomain protein Hlxb9 (Haumaitre et al 2005).…”

Section: Pancreatic Developmentmentioning

confidence: 99%

“…There is no convincing evidence that either HNF1α or Hnf4α have an effect on embryonic growth of the β cell. It is more likely that these genes play a role in regulating key genes in the adult β, and although chromatin immunoprecipitaion studies have shown that HNF1 α can bind more than 10,000 promoters (Odom et al 2004), we still know very little about their targets in the human β cell (Maestro et al 2007). It is also probable that these A c c e p t e d M a n u s c r i p t genes contribute, along with others described below, to the proliferative response of adult β cells that forms part of a compensatory or survival strategy.…”

Section: Maintenance Of β Cell Functionmentioning

confidence: 99%

Pancreatic transcription factors and their role in the birth, life and survival of the pancreatic β cell

Bernardo¹,

Hay²,

Docherty³

2008

Molecular and Cellular Endocrinology

148

123

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In recent years major progress has been made in understanding the role of transcription factors in the development of the endocrine pancreas in the mouse. Here we describe how a number of these transcription factors play a role in maintaining the differentiated phenotype of the β cell, and in the mechanisms that allow the β cell to adapt to changing metabolic demands that occur throughout life. Amongst these factors, Pdx1 plays a critical role in defining the region of the primitive gut that will form the pancreas, Ngn3 expression drives cells towards an endocrine lineage, and a number of additional proteins including Pdx1, in a second wave of expression, Pax4, NeuroD1/β2, and MafA act as β cell differentiation factors. In the mature β cell Pdx1, MafA, β2, and Nkx2.2 play important roles in regulating expression of insulin and to some extent other genes responsible for maintaining β cell function. We emphasise here that data from gene expression studies in rodents seldom map on to the known structure of the corresponding human promoters. In the adult the β cell is particularly susceptible to autoimmune mediated attack and to the toxic metabolic milieu associated with over-eating, and utilises a number of these transcription factors in its defence. Pdx1 has anti-apoptotic and proliferative activities that help facilitate the maintenance of β cell mass, while Ngn3 may be involved in the recruitment of progenitor cells, and Pax4 (and possibly HNF1α and Hnf4α) in the proliferation of β cells in the adult pancreas. Other transcription factors with a more widespread pattern of expression that play a role in β survival or proliferation include Foxo1, CREB family members, NFAT, FoxM1, Snail and Asc-2.2

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“…Using MODY-hiPSCs from nondiabetic mutation carriers further offers the potential advantage of studying prediabetic cell biology. HNF4A (MODY1), HNF1A (MODY3), and HNF1B (MODY5) are members of the hepatocyte nuclear factor (HNF) family, implicated in pancreas development and function (8). HNF4A is important for the development and function of both beta cells and hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Derivation of Human Induced Pluripotent Stem Cells from Patients with Maturity Onset Diabetes of the Young*

Teo

Windmueller

Johansson

et al. 2013

Journal of Biological Chemistry

107

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Background: Human induced pluripotent stem cells (hiPSCs) can be harnessed for development of novel therapeutics for metabolic disorders. Results: Karyotypically normal hiPSCs were derived from patients with MODY1, MODY2, MODY3, MODY5, or MODY8. Conclusion: hiPSCs were successfully derived from a variety of MODY patients. Significance: MODY-hiPSCs can be used to explore the role of MODY genes in the development and function of pancreatic islet cells. Maturity onset diabetes of the young (MODY) is an autosomal dominant disease. Despite extensive research, the mechanism by which a mutant MODY gene results in monogenic diabetesis not yet clear due to the inaccessibility of patient samples. Induced pluripotency and directed differentiation toward the pancreatic lineage are now viable and attractive methods to uncover the molecular mechanisms underlying MODY. Here we report, for the first time, the derivation of human induced pluripotent stem cells (hiPSCs) from patients with five types of MODY: MODY1 (HNF4A), MODY2 (GCK), MODY3 (HNF1A), MODY5 (HNF1B), and MODY8 (CEL) with a polycistronic lentiviral vector expressing a Cre-excisable human "stem cell cassette" containing the four reprogramming factors OCT4, KLF4, SOX2, and CMYC. These MODY-hiPSCs morphologically resemble human pluripotent stem cells (hPSCs), express pluripotency markers OCT4, SOX2, NANOG, SSEA-4, and TRA-1-60, give rise to derivatives of the three germ layers in a teratoma assay, and are karyotypically normal. Overall, our MODYhiPSCs serve as invaluable tools to dissect the role of MODY genes in the development of pancreas and islet cells and to evaluate their significance in regulating beta cell function. This knowledge will aid future attempts aimed at deriving functional mature beta cells from hPSCs. Maturity onset diabetes of the young (MODY)2 is an autosomal dominant monogenic diabetic disease typically affecting individuals before the age of 25 years. To date, 11 MODY genes have been identified, comprising both transcription factors and enzymes/hormones: MODY1 (HNF4A), MODY2 (GCK), MODY3 (HNF1A), MODY4 (PDX1), MODY5 (HNF1B), MODY6 (NEUROD1), MODY7 (KLF11), MODY8 (CEL), MODY9 (PAX4), MODY10 (INS), and MODY11 (BLK) (1). Various disease-causing genetic variants have been identified for each of the MODY genes, all of which affect pancreas and beta cell development, ultimately resulting in beta cell dysfunction and diabetes.The advent of induced pluripotency (2) has provided an opportunity to derive human induced pluripotent stem cells (hiPSCs) from MODY patients to model the disease in vitro. Several studies have reported that human somatic cells, commonly skin fibroblasts, can be reprogrammed into hiPSCs. A number of groups have reported the generation of hiPSCs from patients with mitochondrial diabetes, type 1 and type 2 diabetes mellitus (3, 4). However, given the complexity of type 1 and type 2 diabetes mellitus, the use of hiPSCs from these patients requires comparison with multiple controls that are appropriate for the genetic and environmenta...

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Distinct Roles of HNF1 Β , HNF1 α , and HNF4 α in Regulating Pancreas Development, Β -Cell Function and Growth

Cited by 106 publications

References 67 publications

Visfatin regulates insulin secretion, insulin receptor signalling and mRNA expression of diabetes-related genes in mouse pancreatic β-cells

Visfatin regulates insulin secretion, insulin receptor signalling and mRNA expression of diabetes-related genes in mouse pancreatic β-cells

Pancreatic transcription factors and their role in the birth, life and survival of the pancreatic β cell

Derivation of Human Induced Pluripotent Stem Cells from Patients with Maturity Onset Diabetes of the Young*

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