Inactivation of the winged helix transcription factor HNF3alpha affects glucose homeostasis and islet glucagon gene expression in vivo.
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.
Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6145, USA. kaestner@mail.med.upenn.edu
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Kaestner
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Katz
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Liu
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Drucker
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Schütz
D000818:Animals; D001835:Body Weight / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation / Q000235:genetics; D018390:Gene Targeting; D017930:Genes, Reporter / Q000235:genetics; D005934:Glucagon / Q000097:blood / Q000235:genetics*; D005938:Glucocorticoids / Q000097:blood; D005943:Gluconeogenesis / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D051541:Hepatocyte Nuclear Factor 3-alpha; D006651:Histocytochemistry; D006706:Homeostasis / Q000502:physiology; D007003:Hypoglycemia / Q000235:genetics; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics*; D052336:Proglucagon; D011401:Promoter Regions, Genetic / Q000235:genetics; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics
D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C496500:Foxa1 protein, mouse; C486412:Foxf2 protein, mouse; D005938:Glucocorticoids; D051541:Hepatocyte Nuclear Factor 3-alpha; D007328:Insulin; C114562:LUN protein, vertebrate; D009687:Nuclear Proteins; D011498:Protein Precursors; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; D052336:Proglucagon; D005934:Glucagon; D005947:Glucose