Distinct roles of HNF1β, HNF1α, and HNF4α in regulating pancreas development, β-cell function and growth

Mutations in the genes encoding transcriptional regulators HNF1 beta (TCF2), HNF1 alpha (TCF1), and HNF4 alpha 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 HNF1 beta is a critical regulator of a transcriptional network that controls the specification, growth, and differentiation of the embryonic pancreas. HNF1 beta mutations in humans accordingly often cause pancreas hypoplasia. By contrast, HNF1 alpha and HNF4 alpha have been shown to regulate the function of differentiated beta-cells. HNF1 alpha and HNF4 alpha mutations in patients thus cause decreased glucose-induced insulin secretion that leads to a progressive form of diabetes. HNF4 alpha mutations paradoxically also cause in utero and neonatal hyperinsulinism, which later evolves to decreased glucose-induced secretion. Recent studies show that Hnf4 alpha 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 Hnf1 alpha(-/-) beta-cells expressing SV40 large T antigen show a severe impairment of proliferation and failure to form tumours. Collectively, these findings implicate HNF1 beta as a regulator of pancreas organogenesis and differentiation, whereas HNF1 alpha and HNF4 alpha primarily regulate both growth and function of islet beta-cells. Copyright (c) 2007 S. Karger AG, Basel.