PUBLICATION

Metabolic Regulation of Cellular Plasticity in the Pancreas

Authors
Ninov, N., Hesselson, D., Gut, P., Zhou, A., Fidelin, K., and Stainier, D.Y.
ID
ZDB-PUB-130710-45
Date
2013
Source
Current biology : CB   23(13): 1242-50 (Journal)
Registered Authors
Gut, Philipp, Hesselson, Daniel, Ninov, Nikolay, Stainier, Didier
Keywords
none
MeSH Terms
  • Signal Transduction
  • Insulin-Secreting Cells/cytology*
  • Insulin-Secreting Cells/metabolism*
  • Stem Cells/cytology
  • Stem Cells/metabolism
  • Ubiquitination
  • Receptors, Notch/metabolism
  • Cell Differentiation*
  • Zebrafish/growth & development
  • Zebrafish/physiology*
  • TOR Serine-Threonine Kinases/metabolism
  • Animal Nutritional Physiological Phenomena
  • Luminescent Proteins/metabolism
  • Animals, Genetically Modified/growth & development
  • Animals, Genetically Modified/physiology
  • Animals
  • Larva/growth & development
  • Larva/physiology
  • Pancreatic Ducts/cytology
  • Pancreatic Ducts/metabolism
  • Cell Proliferation*
  • Zebrafish Proteins/metabolism
(all 22)
PubMed
23791726 Full text @ Curr. Biol.
Abstract

Obese individuals exhibit an increase in pancreatic β cell mass; conversely, scarce nutrition during pregnancy has been linked to β cell insufficiency in the offspring [reviewed in 1 and 2]. These phenomena are thought to be mediated mainly through effects on β cell proliferation, given that a nutrient-sensitive β cell progenitor population in the pancreas has not been identified. Here, we employed the fluorescent ubiquitination-based cell-cycle indicator system to investigate β cell replication in real time and found that high nutrient concentrations induce rapid β cell proliferation. Importantly, we found that high nutrient concentrations also stimulate β cell differentiation from progenitors in the intrapancreatic duct (IPD). Furthermore, using a new zebrafish line where β cells are constitutively ablated, we show that β cell loss and high nutrient intake synergistically activate these progenitors. At the cellular level, this activation process causes ductal cell reorganization as it stimulates their proliferation and differentiation. Notably, we link the nutrient-dependent activation of these progenitors to a downregulation of Notch signaling specifically within the IPD. Furthermore, we show that the nutrient sensor mechanistic target of rapamycin (mTOR) is required for endocrine differentiation from the IPD under physiological conditions as well as in the diabetic state. Thus, this study reveals critical insights into how cells modulate their plasticity in response to metabolic cues and identifies nutrient-sensitive progenitors in the mature pancreas.

Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
cz1701TgTransgenic Insertion
    nl1TgTransgenic Insertion
      s896TgTransgenic Insertion
        s924TgTransgenic Insertion
          s934TgTransgenic Insertion
            s939TgTransgenic Insertion
              s940TgTransgenic Insertion
                s946TgTransgenic Insertion
                  s948TgTransgenic Insertion
                    s949TgTransgenic Insertion
                      1 - 10 of 15
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                      Human Disease / Model
                      No data available
                      Sequence Targeting Reagents
                      No data available
                      Fish
                      Antibodies
                      Name Type Antigen Genes Isotypes Host Organism
                      Ab-2F11monoclonalIgG1Mouse
                      1 - 1 of 1
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                      Orthology
                      No data available
                      Engineered Foreign Genes
                      Marker Marker Type Name
                      BFPEFGBFP
                      CeruleanEFGCerulean
                      CreEFGCre
                      DsRedEFGDsRed
                      EGFPEFGEGFP
                      GFPEFGGFP
                      KaedeEFGKaede
                      mAGFPEFGmAGFP
                      mCherryEFGmCherry
                      VenusEFGVenus
                      1 - 10 of 10
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                      Mapping
                      No data available