PUBLICATION

Whole organism small molecule screen identifies novel regulators of pancreatic endocrine development

Authors
Helker, C.S.M., Mullapudi, S.T., Mueller, L.M., Preussner, J., Tunaru, S., Skog, O., Kwon, H.B., Kreuder, F., Lancman, J.J., Bonnavion, R., Dong, P.D.S., Looso, M., Offermanns, S., Korsgren, O., Spagnoli, F.M., Stainier, D.Y.R.
ID
ZDB-PUB-190601-2
Date
2019
Source
Development (Cambridge, England)   146(14): (Journal)
Registered Authors
Dong, P. Duc, Helker, Christian, Lancman, Joseph, Stainier, Didier
Keywords
Pdx1, Small molecule screen, Transdifferentiation, α-cells, β-cells
MeSH Terms
  • Islets of Langerhans/drug effects
  • Islets of Langerhans/embryology*
  • Islets of Langerhans/growth & development
  • Islets of Langerhans/metabolism
  • Mice, Inbred C57BL
  • Organogenesis/drug effects*
  • Organogenesis/genetics
  • Animals, Genetically Modified
  • Gene Expression Regulation, Developmental/drug effects
  • Trans-Activators/genetics
  • Trans-Activators/metabolism
  • Animals
  • Histone Deacetylase Inhibitors/isolation & purification
  • Histone Deacetylase Inhibitors/pharmacology
  • Zebrafish*/embryology
  • Zebrafish*/genetics
  • Models, Animal*
  • COS Cells
  • Homeodomain Proteins/genetics
  • Homeodomain Proteins/metabolism
  • Insulin-Secreting Cells/cytology
  • Insulin-Secreting Cells/drug effects
  • Insulin-Secreting Cells/physiology
  • Chlorocebus aethiops
  • Cell Transdifferentiation/drug effects
  • Cell Transdifferentiation/genetics
  • Mice
  • Cells, Cultured
  • Embryo, Nonmammalian
  • Humans
  • Small Molecule Libraries/analysis*
  • Small Molecule Libraries/isolation & purification
  • Drug Evaluation, Preclinical/methods*
  • Valproic Acid/isolation & purification
  • Valproic Acid/pharmacology
  • Cell Differentiation/drug effects
  • Cell Differentiation/physiology
(all 37)
PubMed
31142539 Full text @ Development
Abstract
An early step in pancreas development is marked by the expression of the Pdx1 transcription factor within the pancreatic endoderm where it is required for the specification of all endocrine cell types. Subsequently, Pdx1 expression becomes restricted to the β-cell lineage where it plays a central role in β-cell function. This pivotal role of Pdx1 at various stages of pancreas development makes it an attractive target to enhance pancreatic β-cell differentiation and increase β-cell function. In this study, we used a newly generated zebrafish reporter to screen over 8,000 small molecules for modulators of pdx1 expression. We found four hit compounds and validated their efficacy at different stages of pancreas development. Valproic acid (VPA), a HDAC inhibitor, induces pancreatic endoderm formation, while inhibition of TGF-β signaling leads to the transdifferentiation of α-cells to β-cells. HC Toxin, another HDAC inhibitor, enhances β-cell function in primary mouse and human islets. Thus, using a whole-organism screening strategy, this study identified new pdx1 expression modulators which can be used to influence different steps in pancreas and β-cell development.
Genes / Markers
Figures
Figure Gallery (4 images)
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Expression
No data available
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
as3TgTransgenic Insertion
    bns13TgTransgenic Insertion
      bns17TgTransgenic Insertion
        bns102
          		Small Deletion
          bns152TgTransgenic Insertion
            bns250TgTransgenic Insertion
              jh6TgTransgenic Insertion
                jh63TgTransgenic Insertion
                  m1018TgTransgenic Insertion
                    nl1TgTransgenic Insertion
                      1 - 10 of 16
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                      Human Disease / Model
                      No data available
                      Sequence Targeting Reagents
                      No data available
                      Fish
                      No data available
                      Antibodies
                      Name Type Antigen Genes Isotypes Host Organism
                      Ab1-pdx1polyclonalGuinea pig
                      Ab2-nkx6monoclonalIgG1Mouse
                      1 - 2 of 2
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                      Orthology
                      No data available
                      Engineered Foreign Genes
                      Marker Marker Type Name
                      CeruleanEFGCerulean
                      CFPEFGCFP
                      CreEFGCre
                      DsRedEFGDsRed
                      EGFPEFGEGFP
                      GFPEFGGFP
                      KaedeEFGKaede
                      LuciferaseEFGLuciferase
                      mCherryEFGmCherry
                      NTREFGNTR
                      1 - 10 of 11
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                      Mapping
                      No data available
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                      Citation
                      Helker, C.S.M., Mullapudi, S.T., Mueller, L.M., Preussner, J., Tunaru, S., Skog, O., Kwon, H.B., Kreuder, F., Lancman, J.J., Bonnavion, R., Dong, P.D.S., Looso, M., Offermanns, S., Korsgren, O., Spagnoli, F.M., Stainier, D.Y.R. (2019) Whole organism small molecule screen identifies novel regulators of pancreatic endocrine development. Development (Cambridge, England). 146(14):.