Distinct Roles of HNF1beta, HNF1alhpa, and HNF4alpha in Regulating Pancreas Dewelopment, beta-Cell Function and Growth

摘要

Mutations in the genes encoding transcriptional regulators HNF1 (3 (TCF2), HNFIa (TCF1), and HNF4a 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 (3 is a critical regulator of a transcriptional network that controls the specification, growth, and differentiation of the embryonic pancreas. HNF1 (3 mutations in humans accordingly often cause pancreas hypoplasia. By contrast, HNFIa and HNF4ct have been shown to regulate the function of differentiated beta-cells. HNFIa and HNF4a mutations in patients thus cause decreased glucose-induced insulin secretion that leads to a progressive form of diabetes. HNF4ct mutations paradoxically also cause in utero and neonatal hyperinsulinism, which later evolves to decreased glucose-induced secretion. Recent studies show that Hnf4a 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 Hnf1a~(-/-) 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 HNFIa and HNF4a primarily regulate both growth and function of islet beta-cells.