Document Detail


The FoxM1 transcription factor is required to maintain pancreatic beta-cell mass.
MedLine Citation:
PMID:  16556734     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The FoxM1 transcription factor is highly expressed in proliferating cells and activates several cell cycle genes, although its requirement appears to be limited to certain tissue types. Embryonic hepatoblast-specific inactivation of Foxm1 results in a dramatic reduction in liver outgrowth and subsequent late gestation lethality, whereas inactivation of Foxm1 in adult liver impairs regeneration after partial hepatectomy. These results prompted us to examine whether FoxM1 functions similarly in embryonic outgrowth of the pancreas and beta-cell proliferation in the adult. We found that FoxM1 is highly expressed in embryonic and neonatal endocrine cells, when many of these cells are proliferating. Using a Cre-lox strategy, we generated mice in which Foxm1 was inactivated throughout the developing pancreatic endoderm by embryonic d 15.5 (Foxm1(Deltapanc)). Mice lacking Foxm1 in their entire pancreas were born with normal pancreatic and beta-cell mass; however, they displayed a gradual decline in beta-cell mass with age. Failure of postnatal beta-cell mass expansion resulted in impaired islet function by 6 wk of age and overt diabetes by 9 wk. The decline in beta-cell mass in Foxm1(Deltapanc) animals is due to a dramatic decrease in postnatal beta-cell replication and a corresponding increase in nuclear localization of the cyclin-dependent kinase inhibitor, p27(Kip1), a known target of FoxM1 inhibition. We conclude that Foxm1 is essential to maintain normal beta-cell mass and regulate postnatal beta-cell turnover. These results suggest that mechanisms regulating embryonic beta-cell proliferation differ from those used postnatally to maintain the differentiated cell population.
Authors:
Hongjie Zhang; Amanda M Ackermann; Galina A Gusarova; David Lowe; Xue Feng; Usa G Kopsombut; Robert H Costa; Maureen Gannon
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2006-03-23
Journal Detail:
Title:  Molecular endocrinology (Baltimore, Md.)     Volume:  20     ISSN:  0888-8809     ISO Abbreviation:  Mol. Endocrinol.     Publication Date:  2006 Aug 
Date Detail:
Created Date:  2006-07-26     Completed Date:  2006-09-28     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  8801431     Medline TA:  Mol Endocrinol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1853-66     Citation Subset:  IM    
Affiliation:
Departments of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Proliferation
Cell Size
Down-Regulation
Forkhead Transcription Factors / genetics,  physiology*
Gene Deletion
Gene Expression
Glucose Tolerance Test
Insulin / biosynthesis
Insulin-Secreting Cells / pathology,  physiology*
Integrases / metabolism
Islets of Langerhans / abnormalities,  cytology,  embryology,  growth & development,  metabolism
Mice
Mice, Knockout
Organ Specificity
Pancreas / abnormalities,  embryology,  growth & development
Time Factors
Transcription Factors / physiology
Grant Support
ID/Acronym/Agency:
R01 DK54687-07/DK/NIDDK NIH HHS; R56 DK071052-01/DK/NIDDK NIH HHS; U24 DK59637/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Forkhead Transcription Factors; 0/Foxm1 protein, mouse; 0/Transcription Factors; 11061-68-0/Insulin; EC 2.7.7.-/Cre recombinase; EC 2.7.7.-/Integrases

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


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