PUBLICATION

glucagon is essential for alpha cell transdifferentiation and beta cell neogenesis

Authors
Ye, L., Robertson, M.A., Hesselson, D., Stainier, D.Y., Anderson, R.M.
ID
ZDB-PUB-150409-3
Date
2015
Source
Development (Cambridge, England)   142: 1407-17 (Journal)
Registered Authors
Anderson, Ryan, Stainier, Didier
Keywords
Alpha cell, Arx, Arxa, Beta cell, GLP-1, Gcga, Glucagon, Insulin, Pancreas, Pancreatic progenitor, Regeneration, Transdifferentiation, Zebrafish
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Cell Proliferation/physiology
  • Cell Transdifferentiation/physiology
  • Glucagon/metabolism*
  • Glucagon-Like Peptide 1/metabolism
  • Glucagon-Secreting Cells/cytology*
  • Glucagon-Secreting Cells/metabolism*
  • Insulin-Secreting Cells/cytology*
  • Insulin-Secreting Cells/metabolism*
  • Pancreas/cytology
  • Pancreas/metabolism
  • Zebrafish
(all 13)
PubMed
25852199 Full text @ Development
Abstract
The interconversion of cell lineages via transdifferentiation is an adaptive mode of tissue regeneration and an appealing therapeutic target. However, its clinical exploitation is contingent upon the discovery of contextual regulators of cell fate acquisition and maintenance. In murine models of diabetes, glucagon-secreting alpha cells transdifferentiate into insulin-secreting beta cells following targeted beta cell depletion, regenerating the form and function of the pancreatic islet. However, the molecular triggers of this mode of regeneration are unknown. Here, using lineage-tracing assays in a transgenic zebrafish model of beta cell ablation, we demonstrate conserved plasticity of alpha cells during islet regeneration. In addition, we show that glucagon expression is upregulated after injury. Through gene knockdown and rescue approaches, we also find that peptides derived from the glucagon gene are necessary for alpha-to-beta cell fate switching. Importantly, whereas beta cell neogenesis was stimulated by glucose, alpha-to-beta cell conversion was not, suggesting that transdifferentiation is not mediated by glucagon/GLP-1 control of hepatic glucose production. Overall, this study supports the hypothesis that alpha cells are an endogenous reservoir of potential new beta cells. It further reveals that glucagon plays an important role in maintaining endocrine cell homeostasis through feedback mechanisms that govern cell fate stability.
Genes / Markers
Figures
Figure Gallery (6 images)
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
ia1TgTransgenic Insertion
    m1018TgTransgenic Insertion
      nl1TgTransgenic Insertion
        s870TgTransgenic Insertion
          s892TgTransgenic Insertion
            s923TgTransgenic Insertion
              s924TgTransgenic Insertion
                s925TgTransgenic Insertion
                  s949TgTransgenic Insertion
                    s950TgTransgenic Insertion
                      1 - 10 of 12
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                      Human Disease / Model
                      No data available
                      Sequence Targeting Reagents
                      Target Reagent Reagent Type
                      arxaMO5-arxaMRPHLNO
                      gcgaMO1-gcgaMRPHLNO
                      1 - 2 of 2
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                      Fish
                      Fish
                      ia1Tg
                      ia1Tg; m1018Tg
                      ia1Tg; m1018Tg + MO1-gcga
                      ia1Tg; m1018Tg; s950Tg
                      m1018Tg
                      nl1Tg
                      s870Tg
                      s892Tg
                      s923Tg
                      s923Tg; s924Tg; s950Tg
                      1 - 10 of 20
                      Show
                      Antibodies
                      Orthology
                      No data available
                      Engineered Foreign Genes
                      Marker Marker Type Name
                      CeruleanEFGCerulean
                      CFPEFGCFP
                      CreEFGCre
                      DsRedEFGDsRed
                      EGFPEFGEGFP
                      GFPEFGGFP
                      KaedeEFGKaede
                      mCherryEFGmCherry
                      NTREFGNTR
                      VenusEFGVenus
                      1 - 10 of 10
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                      Mapping
                      No data available
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                      Citation
                      Ye, L., Robertson, M.A., Hesselson, D., Stainier, D.Y., Anderson, R.M. (2015) glucagon is essential for alpha cell transdifferentiation and beta cell neogenesis. Development (Cambridge, England). 142:1407-17.