PUBLICATION

Retinoic acid plays an evolutionarily conserved and biphasic role in pancreas development

Authors
Huang, W., Wang, G., Delaspre, F., Vitery, M.D., Beer, R.L., Parsons, M.J.
ID
ZDB-PUB-140817-2
Date
2014
Source
Developmental Biology   394(1): 83-93 (Journal)
Registered Authors
Beer, Rebecca, Delaspre, Fabien, Huang, Wei, Parsons, Michael, Wang, Guangliang (Johnny)
Keywords
Differentiation, Pancreas, Progenitors, Retinoic acid
MeSH Terms
  • Signal Transduction
  • Endocrine Cells/metabolism
  • Animals, Genetically Modified
  • Insulin-Secreting Cells/cytology
  • Insulin-Secreting Cells/metabolism*
  • Tretinoin/antagonists & inhibitors
  • Tretinoin/metabolism*
  • Tretinoin/pharmacology
  • Zebrafish/embryology*
  • Cell Differentiation/drug effects
  • Cell Line
  • Gene Expression Regulation, Developmental
  • Animals
  • Pancreas/embryology*
  • Cell Lineage
  • Zebrafish Proteins
  • Organogenesis
  • Receptors, Notch/antagonists & inhibitors
  • Receptors, Notch/metabolism*
(all 19)
PubMed
25127993 Full text @ Dev. Biol.
Abstract
As the developing zebrafish pancreas matures, hormone-producing endocrine cells differentiate from pancreatic Notch-responsive cells (PNCs) that reside within the ducts. These new endocrine cells form small clusters known as secondary (2°) islets. We use the formation of 2° islets in the pancreatic tail of the larval zebrafish as a model of β-cell neogenesis. Pharmacological inhibition of Notch signaling leads to precocious endocrine differentiation and the early appearance of 2° islets in the tail of the pancreas. Following a chemical screen, we discovered that blocking the retinoic acid (RA)-signaling pathway also leads to the induction of 2° islets. Conversely, the addition of exogenous RA blocks the differentiation caused by Notch inhibition. In this report we characterize the interaction of these two pathways. We first verified that signaling via both RA and Notch ligands act together to regulate pancreatic progenitor differentiation. We produced a transgenic RA reporter, which demonstrated that PNCs directly respond to RA signaling through the canonical transcriptional pathway. Next, using a genetic lineage tracing approach, we demonstrated these progenitors produce endocrine cells following inhibition of RA signaling. Lastly, inhibition of RA signaling using a cell-type specific inducible cre/lox system revealed that RA signaling acts cell-autonomously in PNCs to regulate their differentiation. Importantly, the action of RA inhibition on endocrine formation is evolutionarily conserved, as shown by the differentiation of human embryonic stem cells in a model of human pancreas development. Together, these results revealed a biphasic function for RA in pancreatogenesis. As previously shown by others, RA initially plays an essential role during embryogenesis as it patterns the endoderm and specifies the pancreatic field. We reveal here that later in development RA is involved in negatively regulating the further differentiation of pancreatic progenitors and expands upon the developmental mechanisms by which this occurs.
Genes / Markers
Figures
Figure Gallery (10 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
i26
    Point Mutation
    jh11TgTransgenic Insertion
      jh12TgTransgenic Insertion
        jh15TgTransgenic Insertion
          jh29TgTransgenic Insertion
            jh39TgTransgenic Insertion
              jh55TgTransgenic Insertion
                nl1TgTransgenic Insertion
                  ulg515TgTransgenic Insertion
                    1 - 9 of 9
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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
                    Ab1-inspolyclonalGuinea pig
                    Ab2-gcgpolyclonal
                      Rabbit
                      Ab3-sstpolyclonal
                        Rabbit
                        1 - 3 of 3
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                        Orthology
                        No data available
                        Engineered Foreign Genes
                        Marker Marker Type Name
                        CreEFGCre
                        ECFPEFGECFP
                        EGFPEFGEGFP
                        GFPEFGGFP
                        mCherryEFGmCherry
                        QFEFGQF
                        1 - 6 of 6
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                        Mapping
                        No data available