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A Conditional Model Reveals That Induction of Hepatocyte Nuclear Factor-1 in Hnf1-Null Mutant ß-Cells Can Activate Silenced Genes Postnatally, Whereas Overexpression Is Deleterious

¹ Endocrinology Unit, Hospital Clinic of Barcelona, Institut d’Investigacions August Pi i Sunyer, Barcelona, Spain
² Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
³ Department of Biochemistry, Faculty of Medicine, University of Barcelona, Barcelona, Spain

Address correspondence and reprint requests to Jorge Ferrer MD, Endocrinology Unit, Hospital Clinic de Barcelona, Institut d’Investigacions August Pi i Sunyer; Villarroel 170, Barcelona 08036, Spain. E-mail: jferrer{at}clinic.ub.es

Abbreviations: DCoH, dimerization cofactor of HNF1; HNF, hepatocyte nuclear factor; MODY, maturity-onset diabetes of the young; PCD, pterin-4a-carbinolamine dehydratase; tTA, tetracycline-dependent transactivator

Humans with heterozygous loss-of-function mutations in the hepatocyte nuclear factor-1 (HNF1) gene develop ß-cell–deficient diabetes (maturity-onset diabetes of the young type 3), indicating that HNF1 gene dosage is critical in ß-cells. However, whether increased HNF1 expression might be beneficial or deleterious for ß-cells is unknown. Furthermore, although it is clear that HNF1 is required for ß-cell function, it is not known whether this role is cell autonomous or whether there is a restricted developmental time frame for HNF1 to elicit gene activation in ß-cells. To address this, we generated a tetracycline-inducible mouse model that transcribes HNF1 selectively in ß-cells in either wild-type or Hnf1-null backgrounds. Short-term induction of HNF1 in islets from adult Hnf1^–/– mice that did not express HNF1 throughout development resulted in the activation of target genes, indicating that HNF1 has ß-cell–autonomous functions that can be rescued postnatally. However, transgenic induction throughout development, which inevitably resulted in supraphysiological levels of HNF1, strikingly caused a severe reduction of cellular proliferation, increased apoptosis, and consequently ß-cell depletion and diabetes. Thus, HNF1 is sensitive to both reduced and excessive concentrations in ß-cells. This finding illustrates the paramount importance of using the correct concentration of a ß-cell transcription factor in both gene therapy and artificial differentiation strategies.

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