Distinct roles of HNF1beta, HNF1alpha, and HNF4alpha in regulating pancreas development, beta-cell function and growth.
Distinct roles of HNF1beta, HNF1alpha, and HNF4alpha in regulating pancreas development, beta-cell function and growth.
复制标题
DOI：
10.1159/0000109603
复制
发表时间：
2007
期刊：
影响因子：
--
通讯作者：
M. Maestro;C. Cardalda;S. Boj;R. F. Luco;J. Servitja;J. Ferrer
中科院分区：
文献类型：
--
作者：
M. Maestro;C. Cardalda;S. Boj;R. F. Luco;J. Servitja;J. Ferrer
编码转录调节因子HNF 1 β（TCF 2）、HNF 1 α（TCF 1）和HNF 4 α的基因突变会导致常染色体显性遗传糖尿病（也称为年轻人的成熟型糖尿病）。在此，我们回顾了近年来我们所学到的关于这些调节器在发育和成人胰腺的功能。小鼠研究表明，HNF 1 β是一个转录网络的关键调节因子，控制胚胎胰腺的特化、生长和分化。人类HNF 1 β基因突变通常导致胰腺发育不全。相比之下，HNF 1 α和HNF 4 α已被证明可以调节分化的β细胞的功能。因此，患者中的HNF 1 α和HNF 4 α突变导致葡萄糖诱导的胰岛素分泌减少，从而导致糖尿病的进展形式。HNF 4 α突变矛盾的是也会引起子宫内和新生儿高胰岛素血症，随后演变为葡萄糖诱导的分泌减少。最近的研究表明，小鼠中Hnf 4 α缺乏不仅会导致胰岛素分泌异常，还会损害通常在怀孕期间发生的β细胞群的扩张。根据这一发现，我们提供的数据表明，表达SV 40大T抗原的Hnf 1 α-/-β-细胞表现出严重的增殖障碍和无法形成肿瘤。总的来说，这些发现暗示HNF 1 β是胰腺器官发生和分化的调节因子，而HNF 1 α和HNF 4 α主要调节胰岛β细胞的生长和功能。
Mutations in the genes encoding transcriptional regulators HNF1beta (TCF2), HNF1alpha (TCF1), and HNF4alpha 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 HNF1beta is a critical regulator of a transcriptional network that controls the specification, growth, and differentiation of the embryonic pancreas. HNF1beta mutations in humans accordingly often cause pancreas hypoplasia. By contrast, HNF1alpha and HNF4alpha have been shown to regulate the function of differentiated beta-cells. HNF1alpha and HNF4alpha mutations in patients thus cause decreased glucose-induced insulin secretion that leads to a progressive form of diabetes. HNF4alpha mutations paradoxically also cause in utero and neonatal hyperinsulinism, which later evolves to decreased glucose-induced secretion. Recent studies show that Hnf4alpha 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 Hnf1alpha-/- beta-cells expressing SV40 large T antigen show a severe impairment of proliferation and failure to form tumours. Collectively, these findings implicate HNF1beta as a regulator of pancreas organogenesis and differentiation, whereas HNF1alpha and HNF4alpha primarily regulate both growth and function of islet beta-cells.