Apelqvist A, Li H, Sommer L, Beatus P, Anderson D J, Honjo T, Hrabe de Angelis M, Lendahl U, Edlund H
Department of Microbiology, University of Umeå, Sweden.
Nature. 1999 Aug 26;400(6747):877-81. doi: 10.1038/23716.
The pancreas contains both exocrine and endocrine cells, but the molecular mechanisms controlling the differentiation of these cell types are largely unknown. Despite their endodermal origin, pancreatic endocrine cells share several molecular characteristics with neurons, and, like neurons in the central nervous system, differentiating endocrine cells in the pancreas appear in a scattered fashion within a field of progenitor cells. This indicates that they may be generated by lateral specification through Notch signalling. Here, to test this idea, we analysed pancreas development in mice genetically altered at several steps in the Notch signalling pathway. Mice deficient for Delta-like gene 1 (Dll1) or the intracellular mediator RBP-Jkappa showed accelerated differentiation of pancreatic endocrine cells. A similar phenotype was observed in mice over-expressing neurogenin 3 (ngn 3) or the intracellular form of Notch3 (a repressor of Notch signalling). These data provide evidence that ngn3 acts as proendocrine gene and that Notch signalling is critical for the decision between the endocrine and progenitor/exocrine fates in the developing pancreas.
胰腺包含外分泌细胞和内分泌细胞，但控制这些细胞类型分化的分子机制在很大程度上尚不清楚。尽管胰腺内分泌细胞起源于内胚层，但它们与神经元具有一些共同的分子特征，并且与中枢神经系统中的神经元一样，胰腺中正在分化的内分泌细胞在祖细胞区域内呈散在分布。这表明它们可能是通过Notch信号通路的侧向特化产生的。在此，为了验证这一想法，我们分析了在Notch信号通路中几个步骤发生基因改变的小鼠的胰腺发育情况。缺乏Delta样基因1（Dll1）或细胞内介质RBP-Jκ的小鼠表现出胰腺内分泌细胞的加速分化。在过表达神经生成素3（ngn 3）或Notch3细胞内形式（Notch信号的一种抑制剂）的小鼠中也观察到了类似的表型。这些数据提供了证据，表明ngn3作为促内分泌基因发挥作用，并且Notch信号对于发育中的胰腺内分泌和祖细胞/外分泌命运之间的抉择至关重要。
