PUBLICATION

Characterization and regulation of the hb9/mnx1 beta-cell progenitor specific enhancer in zebrafish

Authors
Arkhipova, V., Wendik, B., Devos, N., Ek, O., Peers, B., and Meyer, D.
ID
ZDB-PUB-120326-9
Date
2012
Source
Developmental Biology   365(1): 290-302 (Journal)
Registered Authors
Arkhipova, Valeriya, Devos, Nathalie, Ek, Olivier, Meyer, Dirk, Peers, Bernard, Wendik, Bjoern
Keywords
none
MeSH Terms
  • Homeodomain Proteins/physiology*
  • Animals, Genetically Modified
  • Insulin-Secreting Cells*/cytology
  • Insulin-Secreting Cells*/physiology
  • Eye Proteins/physiology*
  • Islets of Langerhans/cytology
  • Islets of Langerhans/embryology
  • Nerve Tissue Proteins/physiology
  • Zebrafish/embryology*
  • Zebrafish Proteins/physiology*
  • Paired Box Transcription Factors/physiology*
  • Cell Lineage/physiology
  • Signal Transduction
  • Animals
  • Repressor Proteins/physiology*
  • Stem Cells/physiology
  • Basic Helix-Loop-Helix Transcription Factors/physiology
  • Transcription Factors/physiology*
  • Cell Differentiation/physiology
(all 19)
PubMed
22426004 Full text @ Dev. Biol.
Abstract

Differentiation of insulin producing beta-cells is a genetically well defined process that involves functions of various conserved transcription factors. Still, the transcriptional mechanisms underlying specification and determination of beta-cell fate are poorly defined. Here we provide the description of a beta-cell progenitor specific enhancer as a model to study initial steps of beta-cell differentiation. We show that evolutionary non-conserved upstream sequences of the zebrafish hb9 gene are required and sufficient for regulating expression in beta-cells prior to the onset of insulin expression. This enhancer contains binding sites for paired-box transcription factors and two E-boxes that in EMSA studies show interaction with Pax6b and NeuroD, respectively. We show that Pax6b is a potent activator of endodermal hb9 expression and that this activation depends on the beta-cell enhancer. Using genetic approaches we show that pax6b is crucial for maintenance but not induction of pancreatic hb9 transcription. As loss of Pax6b or Hb9 independently results in the loss of insulin expression, the data reveal a novel cross-talk between the two essential regulators of early beta-cell differentiation. While we find that the known pancreatic E-box binding proteins NeuroD and Ngn3 are not required for hb9 expression we also show that removal of both E-boxes selectively eliminates pancreatic specific reporter expression. The data provide evidence for an Ngn3 independent pathway of beta-cell specification that requires function of currently not specified E-box binding factors.

Genes / Markers
Figures
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
m1018TgTransgenic Insertion
    ml2TgTransgenic Insertion
      ml4TgTransgenic Insertion
        ml5TgTransgenic Insertion
          ml6TgTransgenic Insertion
            ml7TgTransgenic Insertion
              ml8TgTransgenic Insertion
                sa86
                  Point Mutation
                  1 - 8 of 8
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                  Human Disease / Model
                  No data available
                  Sequence Targeting Reagents
                  Target Reagent Reagent Type
                  neurod1MO1-neurod1MRPHLNO
                  neurog3MO1-neurog3MRPHLNO
                  pax6bMO5-pax6bMRPHLNO
                  1 - 3 of 3
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                  Fish
                  Antibodies
                  Orthology
                  No data available
                  Engineered Foreign Genes
                  Marker Marker Type Name
                  DsRedEFGDsRed
                  GFPEFGGFP
                  1 - 2 of 2
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                  Mapping
                  No data available