Document Detail


Suppression of Alk8-mediated Bmp signaling cell-autonomously induces pancreatic beta-cells in zebrafish.
MedLine Citation:
PMID:  20080554     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Bmp signaling has been shown to regulate early aspects of pancreas development, but its role in endocrine, and especially beta-cell, differentiation remains unclear. Taking advantage of the ability in zebrafish embryos to cell-autonomously modulate Bmp signaling in single cells, we examined how Bmp signaling regulates the ability of individual endodermal cells to differentiate into beta-cells. We find that specific temporal windows of Bmp signaling prevent beta-cell differentiation. Thus, future dorsal bud-derived beta-cells are sensitive to Bmp signaling specifically during gastrulation and early somitogenesis stages. In contrast, ventral pancreatic cells, which require an early Bmp signal to form, do not produce beta-cells when exposed to Bmp signaling at 50 hpf, a stage when the ventral bud-derived extrapancreatic duct is the main source of new endocrine cells. Importantly, inhibiting Bmp signaling within endodermal cells via genetic means increased the number of beta-cells, at early and late stages. Moreover, inhibition of Bmp signaling in the late stage embryo using dorsomorphin, a chemical inhibitor of Bmp receptors, significantly increased beta-cell neogenesis near the extrapancreatic duct, demonstrating the feasibility of pharmacological approaches to increase beta-cell numbers. Our in vivo single-cell analyses show that whereas Bmp signaling is necessary initially for formation of the ventral pancreas, differentiating endodermal cells need to be protected from exposure to Bmps during specific stages to permit beta-cell differentiation. These results provide important unique insight into the intercellular signaling environment necessary for in vivo and in vitro generation of beta-cells.
Authors:
Won-Suk Chung; Olov Andersson; Richard Row; David Kimelman; Didier Y R Stainier
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-12-29
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  107     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2010-02-05     Completed Date:  2010-03-26     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1142-7     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Activin Receptors, Type I / physiology*
Animals
Base Sequence
Bone Morphogenetic Proteins / physiology*
DNA Primers
Embryonic Induction / physiology*
In Situ Hybridization
Islets of Langerhans / cytology*
Signal Transduction / physiology*
Zebrafish / embryology*
Zebrafish Proteins / physiology*
Grant Support
ID/Acronym/Agency:
DK075032/DK/NIDDK NIH HHS; T32 HD007183/HD/NICHD NIH HHS
Chemical
Reg. No./Substance:
0/Bone Morphogenetic Proteins; 0/DNA Primers; 0/Zebrafish Proteins; EC 2.7.11.30/Activin Receptors, Type I; EC 2.7.11.30/acvr1l protein, zebrafish
Comments/Corrections

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