A conditional model reveals that induction of hepatocyte nuclear factor-1alpha in Hnf1alpha-null mutant beta-cells can activate silenced genes postnatally, whereas overexpression is deleterious.
Humans with heterozygous loss-of-function mutations in the hepatocyte nuclear factor-1alpha (HNF1alpha) gene develop beta-cell-deficient diabetes (maturity-onset diabetes of the young type 3), indicating that HNF1alpha gene dosage is critical in beta-cells. However, whether increased HNF1alpha expression might be beneficial or deleterious for beta-cells is unknown. Furthermore, although it is clear that HNF1alpha is required for beta-cell function, it is not known whether this role is cell autonomous or whether there is a restricted developmental time frame for HNF1alpha to elicit gene activation in beta-cells. To address this, we generated a tetracycline-inducible mouse model that transcribes HNF1alpha selectively in beta-cells in either wild-type or Hnf1alpha-null backgrounds. Short-term induction of HNF1alpha in islets from adult Hnf1alpha(-/-) mice that did not express HNF1alpha throughout development resulted in the activation of target genes, indicating that HNF1alpha has beta-cell-autonomous functions that can be rescued postnatally. However, transgenic induction throughout development, which inevitably resulted in supraphysiological levels of HNF1alpha, strikingly caused a severe reduction of cellular proliferation, increased apoptosis, and consequently beta-cell depletion and diabetes. Thus, HNF1alpha is sensitive to both reduced and excessive concentrations in beta-cells. This finding illustrates the paramount importance of using the correct concentration of a beta-cell transcription factor in both gene therapy and artificial differentiation strategies.
Luco
Reini F
RF
Endocrinology Unit, Hospital Clinic de Barcelona, Institut d'Investigacions August Pi i Sunyer, Villarroel 170, Barcelona 08036, Spain.
Maestro
Miguel A
MA
del Pozo
Natalia
N
Philbrick
William M
WM
de la Ossa
Pablo Perez
PP
Ferrer
Jorge
J
D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000209:etiology / Q000473:pathology; D005455:Fluorescent Antibody Technique; D018628:Gene Dosage; D005786:Gene Expression Regulation / Q000187:drug effects; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D007515:Islets of Langerhans / Q000473:pathology / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013752:Tetracycline / Q000494:pharmacology; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; D013752:Tetracycline