Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, Neuherberg, Germany.
German Center for Diabetes Research, Neuherberg, Germany.
Diabetes. 2020 May;69(5):915-926. doi: 10.2337/db19-0795. Epub 2020 Feb 6.
Genes of the Notch signaling pathway are expressed in different cell types and organs at different time points during embryonic development and adulthood. The Notch ligand Delta-like 1 (DLL1) controls the decision between endocrine and exocrine fates of multipotent progenitors in the developing pancreas, and loss of leads to premature endocrine differentiation. However, the role of Delta-Notch signaling in adult tissue homeostasis is not well understood. Here, we describe the spatial expression pattern of Notch pathway components in adult murine pancreatic islets and show that DLL1 and DLL4 are specifically expressed in β-cells, whereas JAGGED1 is expressed in α-cells. We show that mice lacking both DLL1 and DLL4 in adult β-cells display improved glucose tolerance, increased glucose-stimulated insulin secretion, and hyperglucagonemia. In contrast, overexpression of the intracellular domain of DLL1 in adult murine pancreatic β-cells results in impaired glucose tolerance and reduced insulin secretion, both in vitro and in vivo. These results suggest that Notch ligands play specific roles in the adult pancreas and highlight a novel function of the Delta/Notch pathway in β-cell insulin secretion.
Notch 信号通路的基因在胚胎发育和成年期的不同时间点在不同的细胞类型和器官中表达。Notch 配体 Delta-like 1（DLL1）控制着发育中的胰腺多能祖细胞中内分泌和外分泌命运的决定，而的缺失导致过早的内分泌分化。然而，Delta-Notch 信号在成人组织稳态中的作用尚不清楚。在这里，我们描述了 Notch 途径成分在成年鼠胰岛中的空间表达模式，并表明 DLL1 和 DLL4 特异性表达于β细胞，而 JAGGED1 表达于α细胞。我们表明，成年β细胞中缺乏 DLL1 和 DLL4 的小鼠表现出改善的葡萄糖耐量、增加的葡萄糖刺激的胰岛素分泌和高胰高血糖素血症。相比之下，DLL1 细胞内结构域在成年鼠胰岛β细胞中的过表达导致体外和体内的葡萄糖耐量受损和胰岛素分泌减少。这些结果表明，Notch 配体在成年胰腺中发挥特定作用，并强调了 Delta/Notch 途径在β细胞胰岛素分泌中的新功能。
