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PMID: 10049364 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Inactivation of the winged helix transcription factor HNF3alpha affects glucose homeostasis and islet glucagon gene expression in vivo.

Genes & development ·Vol. 13 ·No. 4 ·1999-02-15 ·Pages 495-504

Kaestner KH, Katz J, Liu Y, Drucker DJ, Schütz G

Abstract

Mice homozygous for a null mutation in the winged helix transcription factor HNF3alpha showed severe postnatal growth retardation followed by death between P2 and P12. Homozygous mutant mice were hypoglycemic despite unchanged expression of HNF3 target genes involved in hepatic gluconeogenesis. Whereas insulin and corticosteroid levels were altered as expected, plasma glucagon was reduced markedly in the mutant animals despite the hypoglycemia that should be expected to increase glucagon levels. This correlated with a 70% reduction in pancreatic proglucagon gene expression. We also showed that HNF3alpha could bind to and transactivate the proglucagon gene promoter. These observations invoke a central role for HNF3alpha in the regulatory control of islet genes essential for glucose homeostasis in vivo.

MeSH Terms
Animals Body Weight/genetics DNA-Binding Proteins/genetics Forkhead Transcription Factors Gene Expression Regulation/genetics Gene Targeting Genes, Reporter/genetics Glucagon/blood,genetics Glucocorticoids/blood Gluconeogenesis/genetics Glucose/metabolism Hepatocyte Nuclear Factor 3-alpha Histocytochemistry Homeostasis/physiology Hypoglycemia/genetics Insulin/blood Islets of Langerhans/metabolism Mice Mice, Knockout Nuclear Proteins/genetics Proglucagon Promoter Regions, Genetic/genetics Protein Precursors/genetics RNA, Messenger/metabolism Trans-Activators/genetics Transcription Factors/genetics Transcriptional Activation/genetics
Chemicals
DNA-Binding Proteins Forkhead Transcription Factors Foxa1 protein, mouse Foxf2 protein, mouse Glucocorticoids Hepatocyte Nuclear Factor 3-alpha Insulin LUN protein, vertebrate Nuclear Proteins Protein Precursors RNA, Messenger Trans-Activators Transcription Factors Proglucagon Glucagon Glucose
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Kaestner K H
Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6145, USA. [email protected]
Katz J
Liu Y
Drucker D J
Schütz G
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.13.4.495
Email
[email protected]
Published
1999-02-15
Pages
495-504
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC316473
Subset
IM
Grants
NIDDK NIH HHS · P30 DK050306 · United States
NIDDK NIH HHS · R01 DK055342 · United States
NIDDK NIH HHS · P30 DK50306 · United States
NIDDK NIH HHS · P30 DK019525 · United States
NIDDK NIH HHS · P30 DK19525 · United States
NIDDK NIH HHS · R01 DK55342-01 · United States
External Links
PubMed source DOI: 10.1101/gad.13.4.495 PMC Full Text View journal details
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