Independent development of pancreatic α- and β-cells from Neurogenin3-expressing precursors -: A role for the notch pathway in repression of premature differentiation
Independent development of pancreatic α- and β-cells from Neurogenin3-expressing precursors -: A role for the notch pathway in repression of premature differentiation
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DOI：
10.2337/diabetes.49.2.163
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发表时间：
2000-02-01
期刊：
影响因子：
7.7
通讯作者：
Serup, P
中科院分区：
文献类型：
--
作者：
Jensen, J;Heller, RS;Serup, P
多年来，胰腺β细胞前体的性质和身份一直扑朔迷离。一种模型设想了一种早期的多激素前体，可以同时产生α-细胞和β-细胞以及其他类型的内分泌细胞。另一种选择是，β细胞出现较晚，直接来自表达GLUT2和胰腺十二指肠同源盒因子-1(PDX1)的上皮细胞，在这一阶段也产生腺泡细胞。在这项研究中，我们已经确定了PDX1(+)上皮细胞的一个亚群，其标志是神经生成素3(Ngn3)的表达。NGN3是碱性螺旋-环-螺旋(BHLH)转录因子家族中的一员，被认为在bHLH级联中作用于NeuroD的上游。对Ngn3/配对盒因子6(PAX6)和NeuroD/PAX6共表达的详细分析表明，这两个bHLH因子在一组基本上不重叠的细胞中表达，但这种分析也表明，NeuroD(+)细胞是由瞬时表达Ngn3的细胞产生的。Neurd(+)细胞不表达增殖细胞标志物Ki-67，表明这些细胞是有丝分裂后细胞。相反，Ki-67很容易在Ngn3(+)细胞中检测到。因此，Ngn3(+)细胞符合内分泌前体细胞的标准。这些表达模式支持这样的观点，即α和β细胞都独立于PDX1(+)/Ngn3(+)上皮细胞发育，而不是从GLU(+)/INS+中间期发育。α细胞发育的最早迹象似乎是Brain4的表达，它显然先于Islet-1(Isl1)的表达。基于我们的表达分析，我们提出了一个发育阿尔法和贝塔细胞的基因激活和失活的时间序列，从神经D表达的激活开始。内分泌细胞在神经细胞激活之前离开细胞周期，但在围产期重新进入细胞周期。Notch1在PDX+上皮细胞中的动态表达表明，Notch信号可以抑制神经系统中的NGN-Neurd级联反应，从而防止内分泌细胞的过早分化。
The nature and identity of the pancreatic beta-cell precursor has remained elusive for many years. One model envisions an early multihormonal precursor that gives rise to both alpha- and beta-cells and the other endocrine cell types. Alternatively, beta-cells have been suggested to arise late, directly from the GLUT2- and pancreatic duodenal homeobox factor-1 (PDX1)-expressing epithelium, which gives rise also to the acinar cells during this stage. In this study, we have identified a subset of the PDX1(+) epithelial cells that are marked by expression of Neurogenin3 (Ngn3). Ngn3, a member of the basic helix-loop-helix (bHLH) family of transcription factors, is suggested to act upstream of NeuroD in a bHLH cascade. Detailed analysis of Ngn3/paired box factor 6 (PAX6) and NeuroD/PAX6 co-expression shows that the two bHLH factors are expressed in a largely nonoverlapping set of cells, but such analysis also suggests that the NeuroD(+) cells arise from cells expressing Ngn3 transiently. NeuroD(+) cells do not express Ki-67, a marker of proliferating cells, which shows that these cells are postmitotic. In contrast, Ki-67 is readily detected in Ngn3(+) cells. Thus, Ngn3(+) cells fulfill the criteria for an endocrine precursor cell. These expression patterns support the notion that both alpha- and beta-cells develop independently from PDX1(+)/Ngn3(+) epithelial cells, rather than from GLU(+)/INS+ intermediate stages. The earliest sign of alpha-cell development appears to be Brain4 expression, which apparently precedes Islet-1 (ISL1) expression. Based on our expression analysis, we propose a temporal sequence of gene activation and inactivation for developing alpha- and beta-cells beginning with activation of NeuroD expression. Endocrine cells leave the cell cycle before NeuroD activation, but re-enter the cell cycle at perinatal stages. Dynamic expression of Notch1 in PDX+ epithelial cells suggests that Notch signaling could inhibit a Ngn-NeuroD cascade as seen in the nervous system and thus prevent premature differentiation of endocrine cells.