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  • 1.
    Boucher, Marie-Josée
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Selander, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Carlsson, Lennart
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Phosphorylation marks IPF1/PDX1 protein for degradation by glycogen synthase kinase 3-dependent mechanisms.2006In: The Journal of Biological Chemistry, ISSN 0021-9258, Vol. 281, no 10, p. 6395-403Article in journal (Refereed)
  • 2. Boucher, Marie-Josée
    et al.
    Simoneau, Mélanie
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    The homeodomain-interacting protein kinase 2 regulates insulin promoter factor-1/pancreatic duodenal homeobox-1 transcriptional activity2009In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 150, no 1, p. 87-97Article in journal (Refereed)
    Abstract [en]

    The homeodomain transcription factor insulin promoter factor (IPF)-1/pancreatic duodenal homeobox (PDX)-1 plays a crucial role in both pancreas development and maintenance of beta-cell function. Targeted disruption of the Ipf1/Pdx1 gene in beta-cells of mice leads to overt diabetes and reduced Ipf1/Pdx1 gene expression results in decreased insulin expression and secretion. In humans, mutations in the IPF1 gene have been linked to diabetes. Hence, the identification of molecular mechanisms regulating the transcriptional activity of this key transcription factor is of great interest. Herein we analyzed homeodomain-interacting protein kinase (Hipk) 2 expression in the embryonic and adult pancreas by in situ hybridization and RT-PCR. Moreover, we functionally characterized the role of HIPK2 in regulating IPF1/PDX1 transcriptional activity by performing transient transfection experiments and RNA interference. We show that Hipk2 is expressed in the developing pancreatic epithelium from embryonic d 12-15 but that the expression becomes preferentially confined to pancreatic endocrine cells at later developmental stages. Moreover, we show that HIPK2 positively influences IPF1/PDX1 transcriptional activity and that the kinase activity of HIPK2 is required for this effect. We also demonstrate that HIPK2 directly phosphorylates the C-terminal portion of IPF1/PDX1. Taken together, our data provide evidence for a new mechanism by which IPF1/PDX1 transcriptional activity, and thus possibly pancreas development and/or beta-cell function, is regulated.

  • 3. Correa-Medina, Mayrin
    et al.
    Bravo-Egana, Valia
    Rosero, Samuel
    Ricordi, Camillo
    Diez, Juan
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Pastori, Ricardo L
    MicroRNA miR-7 is preferentially expressed in endocrine cells of the developing and adult human pancreas.2009In: Gene Expression Patterns, ISSN 1567-133X, E-ISSN 1872-7298, Vol. 9, no 4, p. 193-9Article in journal (Refereed)
    Abstract [en]

    MicroRNAs (miRNA) are small non-coding RNAs that inhibit gene expression through binding to complementary messenger RNA sequences. miRNAs have been predicted to target genes important for pancreas development, proper endocrine cell function and metabolism. We previously described that miRNA-7 (miR-7) was the most abundant and differentially expressed islet miRNA, with 200-fold higher expression in mature human islets than in acinar tissue. Here we have analyzed the temporal and spatial expression of miR-7 in human fetal pancreas from 8 to 22 weeks of gestational age (wga). Human fetal (8-22wga) and adult pancreases were processed for immunohistochemistry, in situ hybridization, and quantitative RT-PCR of miRNA and mRNA. miR-7 was expressed in the human developing pancreas from around 9wga and reached its maximum expression levels between 14 and 18wga, coinciding with the exponential increase of the pancreatic endocrine hormones. Throughout development miR-7 expression was preferentially localized to endocrine cells and its expression persisted in the adult pancreas. The present study provides a detailed analysis of the spatiotemporal expression of miR-7 in developing human pancreas. The specific localization of miR-7 expression to fetal and adult endocrine cells indicates a potential role for miR-7 in endocrine cell differentiation and/or function. Future functional studies of a potential role for miR-7 function in islet cell differentiation and physiology are likely to identify novel targets for the treatment of diabetes and will lead to the development of improved protocols for generating insulin-producing cells for cell replacement therapy.

  • 4. Crabtree, Judy S
    et al.
    Scacheri, Peter C
    Ward, Jerrold M
    McNally, Sara R
    Swain, Gary P
    Montagna, Cristina
    Hager, Jeffrey H
    Hanahan, Douglas
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Magnuson, Mark A
    Garrett-Beal, Lisa
    Burns, A Lee
    Ried, Thomas
    Chandrasekharappa, Settara C
    Marx, Stephen J
    Spiegel, Allen M
    Collins, Francis S
    Of mice and MEN1: Insulinomas in a conditional mouse knockout.2003In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 23, no 17, p. 6075-6085Article in journal (Refereed)
    Abstract [en]

    Patients with multiple endocrine neoplasia type 1 (MEN1) develop multiple endocrine tumors, primarily affecting the parathyroid, pituitary, and endocrine pancreas, due to the inactivation of the MEN1 gene. A conditional mouse model was developed to evaluate the loss of the mouse homolog, Men1, in the pancreatic beta cell. Men1 in these mice contains exons 3 to 8 flanked by loxP sites, such that, when the mice are crossed to transgenic mice expressing cre from the rat insulin promoter (RIP-cre), exons 3 to 8 are deleted in beta cells. By 60 weeks of age, >80% of mice homozygous for the floxed Men1 gene and expressing RIP-cre develop multiple pancreatic islet adenomas. The formation of adenomas results in elevated serum insulin levels and decreased blood glucose levels. The delay in tumor appearance, even with early loss of both copies of Men1, implies that additional somatic events are required for adenoma formation in beta cells. Comparative genomic hybridization of beta cell tumor DNA from these mice reveals duplication of chromosome 11, potentially revealing regions of interest with respect to tumorigenesis.

  • 5. Domínguez-Bendala, Juan
    et al.
    Klein, Dagmar
    Ribeiro, Melina
    Ricordi, Camillo
    Inverardi, Luca
    Pastori, Ricardo
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    TAT-mediated neurogenin 3 protein transduction stimulates pancreatic endocrine differentiation in vitro.2005In: Diabetes, ISSN 0012-1797, Vol. 54, no 3, p. 720-6Article in journal (Refereed)
  • 6.
    Edfalk, Sara
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Steneberg, Pär
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion.2008In: Diabetes, ISSN 1939-327X, Vol. 57, no 9, p. 2280-7Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The G-protein-coupled receptor Gpr40 is expressed in beta-cells where it contributes to free fatty acid (FFA) enhancement of glucose-stimulated insulin secretion. However, other sites of Gpr40 expression, including the intestine, have been suggested. The transcription factor IPF1/PDX1 was recently shown to bind to an enhancer element within the 5'-flanking region of Gpr40, implying that IPF1/PDX1 might regulate Gpr40 expression. Here, we addressed whether 1) Gpr40 is expressed in the intestine and 2) Ipf1/Pdx1 function is required for Gpr40 expression. RESEARCH DESIGN AND METHODS: In the present study, Gpr40 expression was monitored by X-gal staining using Gpr40 reporter mice and by in situ hybridization. Ipf1/Pdx1-null and beta-cell specific mutants were used to investigate whether Ipf1/Pdx1 controls Gpr40 expression. Plasma insulin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucose levels in response to acute oral fat diet were determined in Gpr40 mutant and control mice. RESULTS: Here, we show that Gpr40 is expressed in endocrine cells of the gastrointestinal tract, including cells expressing the incretin hormones GLP-1 and GIP, and that Gpr40 mediates FFA-stimulated incretin secretion. We also show that Ipf1/Pdx1 is required for expression of Gpr40 in beta-cells and endocrine cells of the anterior gastrointestinal tract. CONCLUSIONS: Together, our data provide evidence that Gpr40 modulates FFA-stimulated insulin secretion from beta-cells not only directly but also indirectly via regulation of incretin secretion. Moreover, our data suggest a conserved role for Ipf1/Pdx1 and Gpr40 in FFA-mediated secretion of hormones that regulate glucose and overall energy homeostasis.

  • 7. Fujitani, Yoshio
    et al.
    Fujitani, Shuko
    Luo, Huijun
    Qiu, Feng
    Burlison, Jared
    Long, Qiaoming
    Kawaguchi, Yoshiya
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    MacDonald, Raymond J
    Furukawa, Takahisa
    Fujikado, Takashi
    Magnuson, Mark A
    Xiang, Mengqing
    Wright, Christopher V E
    Ptf1a determines horizontal and amacrine cell fates during mouse retinal development.2006In: Development, ISSN 0950-1991, Vol. 133, no 22, p. 4439-50Article in journal (Refereed)
  • 8. Gao, Tao
    et al.
    McKenna, Brian
    Li, Changhong
    Reichert, Maximilian
    Nguyen, James
    Singh, Tarjinder
    Yang, Chenghua
    Pannikar, Archana
    Doliba, Nicolai
    Zhang, Tingting
    Stoffers, Doris A.
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Matschinsky, Franz
    Stein, Roland
    Stanger, Ben Z.
    Pdx1 Maintains beta Cell Identity and Function by Repressing an alpha Cell Program2014In: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 19, no 2, p. 259-271Article in journal (Refereed)
    Abstract [en]

    Pdx1 is a homeobox-containing transcription factor that plays a key role in pancreatic development and adult beta cell function. In this study, we traced the fate of adult beta cells after Pdx1 deletion. As expected, beta-cell-specific removal of Pdx1 resulted in severe hyperglycemia within days. Surprisingly, a large fraction of Pdx1-deleted cells rapidly acquired ultrastructural and physiological features of a cells, indicating that a robust cellular reprogramming had occurred. Reprogrammed cells exhibited a global transcriptional shift that included derepression of the alpha cell transcription factor MafB, resulting in a transcriptional profile that closely resembled that of alpha cells. These findings indicate that Pdx1 acts as a master regulator of beta cell fate by simultaneously activating genes essential for beta cell identity and repressing those associated with alpha cell identity. We discuss the significance of these findings in the context of the emerging notion that loss of beta cell identity contributes to the pathogenesis of type 2 diabetes.

  • 9.
    Goulley, Joan
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Dahl, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Baeza, Nathalie
    Mishina, Yuji
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    BMP4-BMPR1A signaling in beta cells is required for and augments glucose-stimulated insulin secretion.2007In: Cell Metabolism, ISSN 1550-4131, Vol. 5, no 3, p. 207-219Article in journal (Refereed)
  • 10.
    Hart, Alan
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Papadopoulou, Stella
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Fgf10 maintains notch activation, stimulates proliferation, and blocks differentiation of pancreatic epithelial cells.2003In: Developmental Dynamics, ISSN 1058-8388, E-ISSN 1097-0177, Vol. 228, no 2, p. 185-193Article in journal (Refereed)
    Abstract [en]

    The pancreas is an endodermally derived organ that initially appears as a dorsal and ventral protrusion of the primitive gut epithelium. The pancreatic progenitor cells present in these early pancreatic anlagen proliferate and eventually give rise to all pancreatic cell types. The fibroblast growth factor receptor (FGFR) 2b high-affinity ligand FGF10 has been linked to pancreatic epithelial cell proliferation, and we have shown previously that Notch signalling controls pancreatic cell differentiation by means of lateral inhibition. In the developing pancreas, activated intracellular Notch appears to be required for maintaining cells in the progenitor state, in part by blocking the expression of the pro-endocrine gene neurogenin 3 (ngn3), and hence endocrine cell differentiation. Here, we show that persistent expression of Fgf10 in the embryonic pancreas of transgenic mice also inhibits pancreatic cell differentiation, while stimulating pancreatic epithelial cell proliferation. We provide evidence that one of the effects of the persistent expression of Fgf10 in the developing pancreas is maintained Notch activation, which results in impaired expression of ngn3 within the pancreatic epithelium. Together, our data suggest a role for FGF10/FGFR2b signalling in regulation of pancreatic cell proliferation and differentiation and that FGF10/FGFR2b signalling affects the Notch-mediated lateral inhibition pathway.

  • 11.
    Jeon, Jongmin
    et al.
    Diabetes Research Institute, University of Miami Leonard M. Miller School of Medicine.
    Correa-Medina, Mayrin
    Diabetes Research Institute, University of Miami Leonard M. Miller School of Medicine.
    Ricordi, Camillo
    Diabetes Research Institute, University of Miami Leonard M. Miller School of Medicine.
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Diez, Juan A
    Diabetes Research Institute, University of Miami Leonard M. Miller School of Medicine.
    Endocrine cell clustering during human pancreas development2009In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 57, no 9, p. 811-824Article in journal (Refereed)
    Abstract [en]

    The development of efficient, reproducible protocols for directed in vitro differentiation of hES cells into insulin producing beta cells will benefit greatly from increased knowledge regarding the spatiotemporal expression profile of key instructive factors involved in human endocrine cell generation. Human fetal pancreases, from 7 to 21 weeks of gestational age, were collected following consent immediately after pregnancy termination and processed for immunostaining, in situ hybridization and real-time RT-PCR expression analyses. Islet-like structures appear from approximately week 12 and unlike the mixed architecture observed in the adult islets, fetal islets are initially formed predominantly by aggregated insulin or glucagon-expressing cells. The period studied (7-22 weeks) coincides with a decrease in the proliferation and an increase in the differentiation of the progenitor cells, the initiation of NGN3 expression and the appearance of differentiated endocrine cells. The present study provides a detailed characterization of islet formation and expression profiles of key intrinsic and extrinsic factors during human pancreas development. This information is beneficial for the development of efficient protocols that will allow guided in vitro differentiation of hES cells into insulin-producing cells.

  • 12. Li, Yazhou
    et al.
    Cao, Xiemin
    Li, Li-Xin
    Brubaker, Patricia L
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Drucker, Daniel J
    beta-Cell Pdx1 expression is essential for the glucoregulatory, proliferative, and cytoprotective actions of glucagon-like peptide-1.2005In: Diabetes, ISSN 0012-1797, Vol. 54, no 2, p. 482-91Article in journal (Refereed)
  • 13. Mavropoulos, Anastasia
    et al.
    Devos, Nathalie
    Biemar, Frédéric
    Zecchin, Elisabetta
    Argenton, Francesco
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Motte, Patrick
    Martial, Joseph A
    Peers, Bernard
    sox4b is a key player of pancreatic alpha cell differentiation in zebrafish.2005In: Developmental Biology, ISSN 0012-1606, Vol. 285, no 1, p. 211-23Article in journal (Refereed)
  • 14. Medina, Mayrin C.
    et al.
    Molina, Judith
    Gadea, Yelena
    Fachado, Alberto
    Murillo, Monika
    Simovic, Gordana
    Pileggi, Antonello
    Hernandez, Arturo
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Bianco, Antonio C.
    The thyroid hormone-inactivating type III deiodinase is expressed in mouse and human β-cells and its targeted inactivation impairs insulin secretion2011In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 152, no 10, p. 3717-3727Article in journal (Refereed)
    Abstract [en]

    Deiodinases are selenoproteins that activate or inactivate thyroid hormone. During vertebrate development, these pathways control thyroid hormone action in a cell-specific fashion explaining how systemic thyroid hormone can affect local control of tissue embryogenesis. Here we investigated the role of the thyroid hormone-inactivating deiodinase (D3) in pancreatic islet function and glucose homeostasis. D3 expression was determined by real-time PCR, immunofluorescence, and enzyme activity. Embryonic and adult wild-type mice and Mice with targeted disruption of Dio3 gene (D3KO) as well as human fetal pancreas and adult islets were studied. Insulin secretion was evaluated in adult mouse isolated islets. We found Dio3 gene expression and protein highly expressed in embryonic and adult pancreatic islets, predominantly in beta-cells in both humans and mice. However, mRNA levels were barely detectable for both the thyroid hormone-activating deiodinases types 1 and 2. D3KO animals were found to be glucose intolerant due to in vitro and in vivo impaired glucose-stimulated insulin secretion, without changes in peripheral sensitivity to insulin. D3KO neonatal (postnatal day 0) and adult pancreas exhibited reduced total islet area due to reduced beta-cell mass, insulin content, and impaired expression of key beta-cells genes. D3 expression in perinatal pancreatic beta-cells prevents untimely exposure to thyroid hormone, the absence of which leads to impaired beta-cell function and subsequently insulin secretion and glucose homeostasis. An analogous role is likely in humans, given the similar D3 expression pattern.

  • 15.
    Norlin, Stefan
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Nuclear factor-{kappa}B activity in {beta}-cells is required for glucose-stimulated insulin secretion.2005In: Diabetes, ISSN 0012-1797, Vol. 54, no 1, p. 125-32Article in journal (Refereed)
  • 16.
    Oström, Maria
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Loffler, Kelly A
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Edfalk, Sara
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Selander, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Dahl, Ulf
    Ricordi, Camillo
    Jeon, Jongmin
    Correa-Medina, Mayrin
    Diez, Juan
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Retinoic acid promotes the generation of pancreatic endocrine progenitor cells and their further differentiation into beta-cells2008In: PLoS ONE, ISSN 1932-6203, Vol. 3, no 7, p. e2841-Article in journal (Refereed)
    Abstract [en]

    The identification of secreted factors that can selectively stimulate the generation of insulin producing beta-cells from stem and/or progenitor cells represent a significant step in the development of stem cell-based beta-cell replacement therapy. By elucidating the molecular mechanisms that regulate the generation of beta-cells during normal pancreatic development such putative factors may be identified. In the mouse, beta-cells increase markedly in numbers from embryonic day (e) 14.5 and onwards, but the extra-cellular signal(s) that promotes the selective generation of beta-cells at these stages remains to be identified. Here we show that the retinoic acid (RA) synthesizing enzyme Raldh1 is expressed in developing mouse and human pancreas at stages when beta-cells are generated. We also provide evidence that RA induces the generation of Ngn3(+) endocrine progenitor cells and stimulates their further differentiation into beta-cells by activating a program of cell differentiation that recapitulates the normal temporal program of beta-cell differentiation.

  • 17.
    Papadopoulou, Stella
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Attenuated Wnt signaling perturbs pancreatic growth but not pancreatic function.2005In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 54, no 10, p. 2844-2851Article in journal (Refereed)
    Abstract [en]

    Mesenchymal-epithelial interactions are pivotal for proper pancreatic growth and development. We have earlier shown that the fibroblast growth factor (FGF) receptor 2 is expressed in pancreatic progenitor cells and that FGF10, the high-affinity ligand of the FGF receptor 2 isoform FGF receptor 2b, promotes expansion of pancreatic progenitors. The Wnt family of ligands, which signal to the Frizzled (Frz) type receptors, have also been shown to mediate mesenchymal-epithelial interactions and cell proliferation in a variety of different systems. Here, we show that Frz3, like FGF receptor 2, is expressed in the pancreatic epithelium during the proliferative phase of the embryonic pancreas in mice and that overexpression of a dominant-negative form of mouse Frz8 in pancreatic progenitors severely perturbs pancreatic growth. Nevertheless, the transgenic mice remain normoglycemic and display normal glucose tolerance and glucose-stimulated insulin secretion when challenged with exogenous glucose. The maintenance of normoglycemia in these mice appears to be the consequence of a relative increase in endocrine cell number per pancreatic area combined with enhanced insulin biosynthesis and insulin secretion. Collectively, our data provide evidence that Wnt signaling is required for pancreatic growth but not adult beta-cell function.

  • 18. Ricordi, Camillo
    et al.
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Toward a renewable source of pancreatic beta-cells.2008In: Nature biotechnology, ISSN 1546-1696, Vol. 26, no 4, p. 397-8Article in journal (Refereed)
  • 19.
    Sharma, Sandeep K
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Chorell, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Steneberg, Pär
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Vernersson-Lindahl, Emma
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Edlund, Helena
    Wittung-Stafshede, Pernilla
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Insulin-degrading enzyme prevents alpha-synuclein fibril formation in a nonproteolytical manner2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 12531Article in journal (Refereed)
    Abstract [en]

    The insulin-degrading enzyme (IDE) degrades amyloidogenic proteins such as Amyloid β (Aβ) and Islet Amyloid Polypeptide (IAPP), i.e. peptides associated with Alzheimer's disease and type 2 diabetes, respectively. In addition to the protease activity normally associated with IDE function an additional activity involving the formation of stable, irreversible complexes with both Aβ and α-synuclein, an amyloidogenic protein involved in Parkinson's disease, was recently proposed. Here, we have investigated the functional consequences of IDE-α-synuclein interactions in vitro. We demonstrate that IDE in a nonproteolytic manner and at sub-stoichiometric ratios efficiently inhibits α-synuclein fibril formation by binding to α-synuclein oligomers making them inert to amyloid formation. Moreover, we show that, within a defined range of α-synuclein concentrations, interaction with α-synuclein oligomers increases IDE's proteolytic activity on a fluorogenic substrate. We propose that the outcomes of IDE-α-synuclein interactions, i.e. protection against α-synuclein amyloid formation and stimulated IDE protease activity, may be protective in vivo.

  • 20.
    Steneberg, Pär
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Bernardo, Lisandro
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Edfalk, Sara
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Lundberg, Lisa
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Backlund, Fredrik
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Ostenson, Claes-Goran
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    The Type 2 Diabetes-Associated Gene Ide Is Required for Insulin Secretion and Suppression of alpha-Synuclein Levels in beta-Cells2013In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 62, no 6, p. 2004-2014Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies have identified several type 2 diabetes (T2D) risk loci linked to impaired beta-cell function. The identity and function of the causal genes in these susceptibility loci remain, however, elusive. The HHEX/IDE T2D locus is associated with decreased insulin secretion in response to oral glucose stimulation in humans. Here we have assessed beta-cell function in Ide knockout (KO) mice. We find that glucose-stimulated insulin secretion (GSIS) is decreased in Ide KO mice due to impaired replenishment of the releasable pool of granules and that the Ide gene is haploinsufficient. We also show that autophagic flux and microtubule content are reduced in beta-cells of Ide KO mice. One important cellular role for IDE involves the neutralization of amyloidogenic proteins, and we find that a-synuclein and IDE levels are inversely correlated in beta-cells of Ide KO mice and T2D patients. Moreover, we provide evidence that both gain and loss of function of a-synuclein in beta-cells in vivo impair not only GSIS but also autophagy. Together, these data identify the Ide gene as a regulator of GSIS, suggest a molecular mechanism for beta-cell degeneration as a consequence of Ide deficiency, and corroborate and extend a previously established important role for a-synuclein in beta-cell function.

  • 21.
    Steneberg, Pär
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Rubins, Nir
    Bartoov-Shifman, Reut
    Walker, Michael D
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis, and impaired glucose homeostasis in mouse.2005In: Cell Metabolism, ISSN 1550-4131, Vol. 1, no 4, p. 245-58Article in journal (Refereed)
  • 22.
    Svensson, Per
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Bergqvist, Ingela
    Norlin, Stefan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    MFng is dispensable for mouse pancreas development and function2009In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 29, no 8, p. 2129-2138Article in journal (Refereed)
    Abstract [en]

    Notch signaling regulates pancreatic cell differentiation, and mutations of various Notch signaling components result in perturbed pancreas development. Members of the Fringe family of beta1,3-N-acetylglucosaminyltransferases, Manic Fringe (MFng), Lunatic Fringe (LFng), and Radical Fringe (RFng), modulate Notch signaling, and MFng has been suggested to regulate pancreatic endocrine cell differentiation. We have characterized the expression of the three mouse Fringe genes in the developing mouse pancreas between embryonic days 9 and 14 and show that the expression of MFng colocalized with the proendocrine transcription factor Ngn3. In contrast, the expression of LFng colocalized with the exocrine marker Ptf1a, whereas RFng was not expressed. Moreover, we show that expression of MFng is lost in Ngn3 mutant mice, providing evidence that MFng is genetically downstream of Ngn3. Gain- and loss-of-function analyses of MFng by the generation of mice that overexpress MFng in early pancreatic progenitor cells and mice with a targeted deletion of MFng provide, however, evidence that MFng is dispensable for pancreas development and function, since no pancreatic defects in these mice were observed.

  • 23.
    Svensson, Per
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Williams, Cecilia
    Lundeberg, Joakim
    Ryden, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Bergqvist, Ingela
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gene array identification of Ipf1/Pdx1 -/- regulated genes in pancreatic progenitor cells.2007In: BMC Developmental Biology, ISSN 1471-213X, E-ISSN 1471-213X, Vol. 7, no 1, p. 129-Article in journal (Refereed)
1 - 23 of 23
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