Development of the Pancreas and Neonatal Diabetes Distinct Roles of HNF1 Β , HNF1 α , and HNF4 α in Regulating Pancreas Development, Β -Cell Function and Growth Maestro M, Cardalda C, Boj S, Luco R, Servitja J, Ferrer J Shield JPH, Scharfmann R (eds): Development of the Pancreas and Neonatal Diabetes. Endocr Dev. Basel, Karger, 2007, vol 12, pp 33-45 (DOI: 10.1159/000109603)
Abstract: Mutations in the genes encoding transcriptional regulators HNF1ß (TCF2), HNF1a (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 HNF1ß is a critical regulator of a transcriptional network that controls the specification, growth, and differentiation of the embryonic pancreas. HNF1ß mutations in humans accordingly often cause pancreas hypoplasia. By contrast, HNF1a and HNF4a have been shown to regulate the function of differentiated ß-cells. HNF1a and HNF4a mutations in patients thus cause decreased glucose-induced insulin secretion that leads to a progressive form of diabetes. HNF4a mutations paradoxically also cause in utero and neonatal hyperinsulinism, which later evolves to decreased glucose-induced secretion. Recent studies show that Hnf4 a deficiency in mice causes not only abnormal insulin secretion, but also an impairment of the expansion of ß-cell mass that normally occurs during pregnancy. In line with this finding, we present data that Hnf1 a- /- ß-cells expressing SV40 large T antigen show a severe impairment of proliferation and failure to form tumours. Collectively, these findings implicate HNF1ß as a regulator of pancreas organogenesis and differentiation, whereas HNF1a and HNF4a primarily regulate both growth and function of islet ß-cells. |
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