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Role of HNF-1alpha in regulating the expression of genes involved in cellular growth and proliferation in pancreatic beta-cells.

ABSTRACT: Hepatocyte nuclear factor (HNF)-1alpha is a homeodomain-containing transcription factor. Humans heterozygous for mutations in the HNF-1alpha gene develop maturity-onset diabetes of the young (MODY3), which is associated with reduced insulin secretion. The mechanisms responsible for defective glucose-induced insulin secretion due to HNF-1alpha deficiency are complex. In order to explore the relationship between HNF-1alpha and beta-cell proliferation, we have created a novel animal model. Mice lacking one allele of the HNF-1alpha gene were crossed with transgenic mice expressing the large T antigen driven by the rat insulin II promoter (RIP). The resulting mouse strains allowed us to study the effect of HNF-1alpha deficiency on the extensive beta-cell proliferation that occurs in these mice. Our results indicate that deficiency of HNF-1alpha severely constrains the extent of beta-cell proliferation occurring in RIP-Tag mice leading to significant changes in blood glucose concentrations as a result of reduced beta-cell number, insulin content, insulin secretion and intracellular responses in Ca(2+). Furthermore expression profiling studies using immortalized cell lines generated from HNF-1alpha/RIP-Tag mice showed changes in expression of genes involved in cellular growth and proliferation. These results provide insights into the mechanisms whereby HNF-1alpha affects beta-cell function.

SUBMITTER: Uchizono Y

PROVIDER: S-EPMC2782714 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Role of HNF-1alpha in regulating the expression of genes involved in cellular growth and proliferation in pancreatic beta-cells.

Uchizono Yuji Y Baldwin Aaron C AC Sakuma Hiroya H Pugh William W Polonsky Kenneth S KS Hara Manami M

Diabetes research and clinical practice 20090131 1

Hepatocyte nuclear factor (HNF)-1alpha is a homeodomain-containing transcription factor. Humans heterozygous for mutations in the HNF-1alpha gene develop maturity-onset diabetes of the young (MODY3), which is associated with reduced insulin secretion. The mechanisms responsible for defective glucose-induced insulin secretion due to HNF-1alpha deficiency are complex. In order to explore the relationship between HNF-1alpha and beta-cell proliferation, we have created a novel animal model. Mice lac ...[more]

PMID: 19181415

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Project description:Defects in pancreatic beta-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) -1alpha, -3beta, -4alpha, and Pdx-1 contribute in the complex transcriptional circuits within the pancreas that are involved in beta-cell development and function. In mice, a heterozygous mutation in Pdx-1 alone, but not Hnf-1alpha(+/-), Hnf-3beta(+/-), or Hnf-4alpha(+/-), causes impaired glucose-stimulated insulin secretion in mice. To investigate the possible functional relationships between these transcription factors on beta-cell activity in vivo, we generated mice with the following combined heterozygous mutations: Pdx-1(+/-)/Hnf-1alpha(+/-), Pdx-1(+/-)/Hnf-3beta(+/-), Pdx-1(+/-)/Hnf-4alpha(+/-), Hnf-1alpha(+/-)/Hnf-4alpha(+/-), and Hnf-3beta(+/-)/Hnf-4alpha(+/-). The greatest loss in function was in combined heterozygous null alleles of Pdx-1 and Hnf-1alpha (Pdx-1(+/-)/Hnf-1alpha(+/-)), or Pdx-1 and Hnf-3beta (Pdx-1(+/-)/Hnf-3beta(+/-)). 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 beta-cell function in Pdx-1(+/-)/Hnf-3beta(+/-) 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-1alpha(+/-) mice. The islet cell architecture was also abnormal in Pdx-1(+/-)/Hnf-3beta(+/-) and Pdx-1(+/-)/Hnf-1alpha(+/-) 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 beta-cell function. These studies also established polygenic mouse models for investigating the mechanisms contributing to beta-cell dysfunction in diabetes.

Project description:Avian feathers have robust growth and regeneration capability and serve as a useful model for decoding hair morphogenesis and other developmental studies. However, the molecular signaling involved in regulating the development of feather follicles is unclear. The purpose of this study was to investigate the role of the Wnt/β-catenin pathway in regulating feather morphogenesis in embryonic chicks through in ovo injection of different doses of Dickkopf-1 (DKK1, a specific inhibitor of the target of the Wnt/β-catenin pathway). A total of 120 fertilized embryo eggs were randomly divided into 4 treatments, including a noninjection group (control group) and groups injected with 100 μL of phosphate-buffered saline (PBS)/egg (PBS control group), 100 μL of PBS/egg containing 600-ng DKK1/egg (600-ng DKK1 group), and 100-μL PBS/egg containing 1,200-ng DKK1/egg (1,200-ng DKK1 group). Feathers and skin tissues were sampled on embryonic (E) day 15 and the day of hatching to examine the feather mass, diameter and density of feather follicles, and the protein expression of the Wnt/β-catenin pathway. The results showed that, compared with CON and PBS treatment, the injection of DKK1 into the yolk sac of chick embryos had no significant effect on the hatching rate and embryo weight (P > 0.05), while it significantly decreased the relative mass of feathers in the whole body (P < 0.05). The high dose of DKK1 (1,200-ng DKK1/egg) decreased the relative mass of feathers on the back, chest, belly, neck, wings, head, and legs, which was more obvious than that in the 600-ng DKK1 group, which presented a dose-dependent effect. In addition, DKK1 injection significantly downregulated the protein expression levels of β-catenin, transcription factor 4, Cyclin D1, and c-Myc (P < 0.05). The immunofluorescence result of β-catenin was consistent with the Western blotting assay results. Altogether, these observations suggested that the Wnt/β-catenin signaling pathway is involved in regulating feather follicle development and feather growth during the embryonic development of chicks.

Dataset Information

Role of HNF-1alpha in regulating the expression of genes involved in cellular growth and proliferation in pancreatic beta-cells.

Publications

Role of HNF-1alpha in regulating the expression of genes involved in cellular growth and proliferation in pancreatic beta-cells.

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