Role of HNF-1alpha in regulating the expression of genes involved in cellular growth and proliferation in pancreatic beta-cells.
Hepatocyte nuclear factor (HNF)-1alpha is a homeodomain-containing transcription factor. Humans heterozygous for mutations in the HNF-1alpha gene develop maturity-onset diabetes of the young (MODY3), which is associated with reduced insulin secretion. The mechanisms responsible for defective glucose-induced insulin secretion due to HNF-1alpha deficiency are complex. In order to explore the relationship between HNF-1alpha and beta-cell proliferation, we have created a novel animal model. Mice lacking one allele of the HNF-1alpha gene were crossed with transgenic mice expressing the large T antigen driven by the rat insulin II promoter (RIP). The resulting mouse strains allowed us to study the effect of HNF-1alpha deficiency on the extensive beta-cell proliferation that occurs in these mice. Our results indicate that deficiency of HNF-1alpha severely constrains the extent of beta-cell proliferation occurring in RIP-Tag mice leading to significant changes in blood glucose concentrations as a result of reduced beta-cell number, insulin content, insulin secretion and intracellular responses in Ca(2+). Furthermore expression profiling studies using immortalized cell lines generated from HNF-1alpha/RIP-Tag mice showed changes in expression of genes involved in cellular growth and proliferation. These results provide insights into the mechanisms whereby HNF-1alpha affects beta-cell function.
Uchizono
Yuji
Y
Department of Medicine, The University of Chicago, 5841 South Maryland Avenue, MC1027, Chicago, IL 60637, USA.
Baldwin
Aaron C
AC
Sakuma
Hiroya
H
Pugh
William
W
Polonsky
Kenneth S
KS
Hara
Manami
M
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D005434:Flow Cytometry; D005951:Glucose Tolerance Test; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000502:physiology*; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice
D051538:Hepatocyte Nuclear Factor 1-alpha; D007328:Insulin; D002118:Calcium