Laron Dwarfism and Non-Insulin-Dependent Diabetes Mellitus in the Hnf-1α Knockout Mouse

Abstract

Mice deficient in hepatocyte nuclear factor 1 alpha (HNF-1␣) were produced by use of the Cre-loxP recombination system. HNF-1␣-null mice are viable but sterile and exhibit a phenotype reminiscent of both Laron-type dwarfism and non-insulin-dependent diabetes mellitus (NIDDM). In contrast to an earlier HNF-1␣-null mouse line that had been produced by use of standard gene disruption methodology (M. Pontoglio, J. Barra, M. Hadchouel, A. Doyen, C. Kress, J. P. Bach, C. Babinet, and M. Yaniv, Cell 84:575-585, 1996), these mice exhibited no increased mortality and only minimal renal dysfunction during the first 6 months of development. Both dwarfism and NIDDM are most likely due to the loss of expression of insulin-like growth factor I (IGF-I) and lower levels of insulin, resulting in stunted growth and elevated serum glucose levels, respectively. These results confirm the functional significance of the HNF-1␣ regulatory elements that had previously been shown to reside in the promoter regions of both the IGF-I and the insulin genes.

Regulation of the Liver Fatty Acid Binding Protein Gene (L-FABP) by Hepatocyte NuclearFactor 1aplha: alterations in fatty acid homeostasis in HNF1alpha-deficient mice

“…Mice deficient in HNF1α exhibit a phenotype reminiscent of both Laron dwarfism and non-insulin dependent diabetes mellitus (NIDDM) (3). HNF1α-null mice are viable yet sterile and exhibit retarded growth (3). A fraction of HNF1α-null mice die shortly after weaning.…”

Expression profile of MODY3/HNF-1α protein in the developing mouse pancreas

“…However, a previous study using RT-PCR suggested that PDX-1 expression was reduced in HNF-1α (-/-) mice [47]. Since the number of beta cells is decreased in the islets of HNF-1α null mice [15,16], a reduced number of beta cells that express PDX-1 might be a possible explanation for the reduced expression of PDX-1 in the islets. Secondary down-regulation of PDX-1 by hyperglycaemia [38,39] might also account for the discrepancy.…”

“…Consecutive sections (6 µm thick) were cut and collected on glass slides for examination. Transgenic mice with a dominant negative overexpression of mutant human HNF-1α (P291fsinsC-HNF-1α) in beta cells and HNF-1α null mice have been described [16,18,19]. The experimental protocol was approved by the Ethics Review Committee for Animal Experimentation of Osaka University.…”

“…A number of transcription factors are initially expressed during embryogenesis and these factors control the differentiation of pancreatic endocrine and exocrine cells [12,13,14]. Although HNF-1α is involved in insulin secretion [15,16,17,18,19], it might have an additional role during the development of the pancreas. Thirdly, a cascade of transcription factors controls the development of pancreatic beta cells [14,20,21].…”

Role of β-catenin in the adult liver

“…For example, HNF1␣-null mice are dwarf and diabetic. 22 While global analysis of gene expression by microarray was not reported, what is most surprising from the current study is the small number of genes that have altered expression in liver of ␤-catenin liver-null mice. In addition to Glu1, Cyp1a2 and Cyp2e1, expression of the glutamine transporter, ornithine aminotransferase, ammonia transporter, and RhBG genes are also virtually extinguished in these mice.…”