PUBLICATION

An insulin signaling feedback loop regulates pancreas progenitor cell differentiation during islet development and regeneration

Authors
Ye, L., Robertson, M.A., Mastracci, T.L., Anderson, R.M.
ID
ZDB-PUB-151216-14
Date
2016
Source
Developmental Biology   409(2): 354-69 (Journal)
Registered Authors
Anderson, Ryan, Ye, Lihua
Keywords
Development, IRS2, Insulin, Pancreas, Pancreatic progenitor, Regeneration, Zebrafish, pdx1, β cell
MeSH Terms
  • Gene Knockdown Techniques
  • Feedback, Physiological*
  • Animals
  • Stem Cells/cytology*
  • Blastomeres/cytology
  • Blastomeres/metabolism
  • Blastomeres/transplantation
  • Cell Lineage
  • Insulin-Secreting Cells/cytology
  • Islets of Langerhans/cytology
  • Islets of Langerhans/embryology*
  • Trans-Activators/metabolism
  • Insulin/metabolism*
  • Receptor, Insulin/metabolism
  • Homeodomain Proteins/metabolism
  • Cell Differentiation*
  • Regeneration*
  • Endoderm/cytology
  • Endoderm/embryology
  • Endoderm/metabolism
  • Zebrafish/embryology
  • Signal Transduction*
(all 22)
PubMed
26658317 Full text @ Dev. Biol.
Abstract
As one of the key nutrient sensors, insulin signaling plays an important role in integrating environmental energy cues with organism growth. In adult organisms, relative insufficiency of insulin signaling induces compensatory expansion of insulin-secreting pancreatic beta (β) cells. However, little is known about how insulin signaling feedback might influence neogenesis of β cells during embryonic development. Using genetic approaches and a unique cell transplantation system in developing zebrafish, we have uncovered a novel role for insulin signaling in the negative regulation of pancreatic progenitor cell differentiation. Blocking insulin signaling in the pancreatic progenitors hastened the expression of the essential β cell genes insulin and pdx1, and promoted β cell fate at the expense of alpha cell fate. In addition, loss of insulin signaling promoted β cell regeneration and destabilization of alpha cell character. These data indicate that insulin signaling constitutes a tunable mechanism for β cell compensatory plasticity during early development. Moreover, using a novel blastomere-to-larva transplantation strategy, we found that loss of insulin signaling in endoderm-committed blastomeres drove their differentiation into β cells. Furthermore, the extent of this differentiation was dependent on the function of the β cell mass in the host. Altogether, our results indicate that modulation of insulin signaling will be crucial for the development of β cell restoration therapies for diabetics; further clarification of the mechanisms of insulin signaling in β cell progenitors will reveal therapeutic targets for both in vivo and in vitro β cell generation.
Genes / Markers
Figures
Figure Gallery (24 images) / 3
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
a131TgTransgenic Insertion
    ia1TgTransgenic Insertion
      iu2TgTransgenic Insertion
        jh1TgTransgenic Insertion
          m1018TgTransgenic Insertion
            nl1TgTransgenic Insertion
              s844TgTransgenic Insertion
                s870TgTransgenic Insertion
                  s892TgTransgenic Insertion
                    s923TgTransgenic Insertion
                      1 - 10 of 14
                      Show
                      Human Disease / Model
                      No data available
                      Sequence Targeting Reagents
                      Target Reagent Reagent Type
                      insMO2-insMRPHLNO
                      insbMO2-insbMRPHLNO
                      sox32MO1-sox32MRPHLNO
                      1 - 3 of 3
                      Show
                      Fish
                      Antibodies
                      Orthology
                      No data available
                      Engineered Foreign Genes
                      Marker Marker Type Name
                      CeruleanEFGCerulean
                      CFPEFGCFP
                      CreEFGCre
                      DsRedEFGDsRed
                      EGFPEFGEGFP
                      GFPEFGGFP
                      mCherryEFGmCherry
                      NTREFGNTR
                      RFPEFGRFP
                      VenusEFGVenus
                      1 - 10 of 11
                      Show
                      Mapping
                      No data available