Document Detail


Effect of forkhead box O1 (FOXO1) on beta cell development in the human fetal pancreas.
MedLine Citation:
PMID:  20033803     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
AIMS/HYPOTHESIS: Recent studies have demonstrated that in adult murine beta cells the forkhead box O1 (FOXO1) transcription factor regulates proliferation and stress resistance. However, the role of FOXO1 during pancreatic development remains largely unknown. The present study aimed to characterise the expression of the FOXO1 transcription factor in the early to mid-gestation human fetal pancreas and to understand its role in islet cell development. METHODS: Human (8-21 week fetal age) pancreases were examined using immunohistological, quantitative RT-PCR and western blotting. Isolated human (18-21 week) fetal islet epithelial cell clusters were treated with insulin or glucose, or transfected with FOXO1 small interfering RNA (siRNA). RESULTS: Nuclear and cytoplasmic FOXO1 were widely produced during human fetal endocrine pancreatic development, co-localising in cells with the transcription factors pancreatic and duodenal homeobox 1 (PDX-1) and neurogenin 3 (NGN3) as well as cytokeratin 19 (CK19), insulin and glucagon. Treatment with exogenous insulin (50 nmol/l) induced the nuclear exclusion of FOXO1 in both cytokeratin 19 (CK19)(+) (p < 0.01) and insulin(+) cells (p < 0.05) in parallel with increased phospho-Akt (p < 0.05) production. siRNA knockdown of FOXO1 significantly increased the number of NGN3(+) (p < 0.01) and NK6 homeobox 1 (NKX6-1)(+) (p < 0.05) cells in parallel with increases in insulin gene expression (p < 0.03) and C-peptide(+) cells (p < 0.05) and reduced levels of hairy and enhancer of split 1 (HES1) (p < 0.01). CONCLUSIONS/INTERPRETATION: Our results indicate that FOXO1 may negatively regulate beta cell differentiation in the human fetal pancreas by controlling critical transcription factors, including NGN3 and NKX6-1. These data suggest that the manipulation of FOXO1 levels may be a useful tool for improving cell-based strategies for the treatment of diabetes.
Authors:
M Al-Masri; M Krishnamurthy; J Li; G F Fellows; H H Dong; C G Goodyer; R Wang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-12-24
Journal Detail:
Title:  Diabetologia     Volume:  53     ISSN:  1432-0428     ISO Abbreviation:  Diabetologia     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-03-02     Completed Date:  2010-04-23     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0006777     Medline TA:  Diabetologia     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  699-711     Citation Subset:  IM    
Affiliation:
Children's Health Research Institute, University of Western Ontario, London, ON, Canada.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Differentiation
Female
Fetal Development / physiology*
Forkhead Transcription Factors / drug effects,  genetics*,  physiology
Gene Expression Regulation, Developmental
Glucagon / genetics
Humans
Insulin / genetics,  pharmacology
Insulin-Secreting Cells / cytology,  drug effects,  physiology*
Islets of Langerhans / embryology
Mice
Pancreas / embryology*
Pregnancy
RNA, Small Interfering / genetics
Reverse Transcriptase Polymerase Chain Reaction
Transcription Factors / metabolism
Transfection
Grant Support
ID/Acronym/Agency:
//Canadian Institutes of Health Research
Chemical
Reg. No./Substance:
0/FOXO1 protein, human; 0/Forkhead Transcription Factors; 0/RNA, Small Interfering; 0/Transcription Factors; 11061-68-0/Insulin; 9007-92-5/Glucagon

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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