title: Distinct roles of HNF1beta, HNF1alpha, and HNF4alpha in regulating pancreas development, beta-cell function and growth.
abstract: Mutations in the genes encoding transcriptional regulators HNF1beta (TCF2), HNF1alpha (TCF1), and HNF4alpha cause autosomal dominant diabetes (also known as maturity-onset diabetes of the young). Herein, we review what we have learnt during recent years concerning the functions of these regulators in the developing and adult pancreas. Mouse studies have revealed that HNF1beta is a critical regulator of a transcriptional network that controls the specification, growth, and differentiation of the embryonic pancreas. HNF1beta mutations in humans accordingly often cause pancreas hypoplasia. By contrast, HNF1alpha and HNF4alpha have been shown to regulate the function of differentiated beta-cells. HNF1alpha and HNF4alpha mutations in patients thus cause decreased glucose-induced insulin secretion that leads to a progressive form of diabetes. HNF4alpha mutations paradoxically also cause in utero and neonatal hyperinsulinism, which later evolves to decreased glucose-induced secretion. Recent studies show that Hnf4alpha deficiency in mice causes not only abnormal insulin secretion, but also an impairment of the expansion of beta-cell mass that normally occurs during pregnancy. In line with this finding, we present data that Hnf1alpha-/- beta-cells expressing SV40 large T antigen show a severe impairment of proliferation and failure to form tumours. Collectively, these findings implicate HNF1beta as a regulator of pancreas organogenesis and differentiation, whereas HNF1alpha and HNF4alpha primarily regulate both growth and function of islet beta-cells.
authors.affiliation: Genomic Programming of Beta Cells Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Endocrinology, Hospital Clínic de Barcelona, Barcelona , Spain.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Maestro
authors.forename: Carina
authors.initials: C
authors.lastname: Cardalda
authors.forename: Sylvia F
authors.initials: SF
authors.lastname: Boj
authors.forename: Reini F
authors.initials: RF
authors.lastname: Luco
authors.forename: Joan Marc
authors.initials: JM
authors.lastname: Servitja
authors.forename: Jorge
authors.initials: J
authors.lastname: Ferrer
mesh_terms: D002455:Cell Division; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000503:physiopathology*; D018507:Gene Expression Regulation, Developmental; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000502:physiology*; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics / Q000502:physiology*; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D010179:Pancreas / Q000254:growth & development / Q000502:physiology*; D010641:Phenotype
chemical_list: C496592:HNF4A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; D007328:Insulin; D051539:Hepatocyte Nuclear Factor 1-beta