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Development. 2019 Jul 24;146(14). pii: dev172569. doi: 10.1242/dev.172569.

A whole organism small molecule screen identifies novel regulators of pancreatic endocrine development.

Author information

1
Max Planck Institute for Heart and Lung Research, Department of Developmental Genetics, 61231 Bad Nauheim, Germany Christian.Helker@mpi-bn.mpg.de Didier.Stainier@mpi-bn.mpg.de.
2
Philipps-University Marburg, Faculty of Biology, Cell Signaling and Dynamics, 35043 Marburg, Germany.
3
Max Planck Institute for Heart and Lung Research, Department of Developmental Genetics, 61231 Bad Nauheim, Germany.
4
Centre for Stem Cells and Regenerative Medicine, King's College London, London WC2R 2LS, UK.
5
Max Planck Institute for Heart and Lung Research, ECCPS Bioinformatics Core Unit, 61231 Bad Nauheim, Germany.
6
Max Planck Institute for Heart and Lung Research, Department of Pharmacology, 61231 Bad Nauheim, Germany.
7
Biochemistry Institute of the Romanian Academy, Department of Enzymology, Bucharest 060031, Romania.
8
Uppsala University, Department of Immunology, Genetics and Pathology, 751 85 Uppsala, Sweden.
9
Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
10
Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.

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

PMID:
31142539
PMCID:
PMC6679364
[Available on 2020-07-15]
DOI:
10.1242/dev.172569

Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

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