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A whole organism small molecule screen identifies novel regulators of pancreatic endocrine development.
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2019 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 146, no 14, article id dev172569Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2019. Vol. 146, no 14, article id dev172569
Keywords [en]
Pdx1, Small molecule screen, Transdifferentiation, α-Cells, β-Cells
National Category
Developmental Biology
Identifiers
URN: urn:nbn:se:uu:diva-392522DOI: 10.1242/dev.172569ISI: 000478027300013PubMedID: 31142539OAI: oai:DiVA.org:uu-392522DiVA, id: diva2:1348808
Funder
EU, FP7, Seventh Framework Programme, 602587Available from: 2019-09-05 Created: 2019-09-05 Last updated: 2019-09-09Bibliographically approved

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Skog, OskarKorsgren, Olle

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