Abstract
An early step in pancreas development is marked by the expression of the transcription factor Pdx1 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 8000 small molecules for modulators of pdx1 expression. We found four hit compounds and validated their efficacy at different stages of pancreas development. Notably, valproic acid treatment increased pancreatic endoderm formation, while inhibition of TGFβ signaling led to α-cell to β-cell transdifferentiation. 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 that can be used to influence different steps in pancreas and β-cell development.
Keywords:
Pdx1; Small molecule screen; Transdifferentiation; α-Cells; β-Cells.
© 2019. Published by The Company of Biologists Ltd.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Genetically Modified
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COS Cells
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Cell Differentiation / drug effects
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Cell Differentiation / physiology
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Cell Transdifferentiation / drug effects
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Cell Transdifferentiation / genetics
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Cells, Cultured
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Chlorocebus aethiops
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Drug Evaluation, Preclinical / methods*
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Embryo, Nonmammalian
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Gene Expression Regulation, Developmental / drug effects
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Histone Deacetylase Inhibitors / isolation & purification
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Histone Deacetylase Inhibitors / pharmacology
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Insulin-Secreting Cells / cytology
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Insulin-Secreting Cells / drug effects
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Insulin-Secreting Cells / physiology
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Islets of Langerhans / drug effects
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Islets of Langerhans / embryology*
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Islets of Langerhans / growth & development
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Islets of Langerhans / metabolism
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Mice
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Mice, Inbred C57BL
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Models, Animal*
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Organogenesis / drug effects*
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Organogenesis / genetics
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Small Molecule Libraries / analysis*
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Small Molecule Libraries / isolation & purification
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Valproic Acid / isolation & purification
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Valproic Acid / pharmacology
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Zebrafish* / embryology
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Zebrafish* / genetics
Substances
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Histone Deacetylase Inhibitors
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Homeodomain Proteins
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Small Molecule Libraries
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Trans-Activators
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pancreatic and duodenal homeobox 1 protein
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Valproic Acid