Attenuation of FGF signalling in mouse β-cells leads to diabetes
Attenuation of FGF signalling in mouse β-cells leads to diabetes
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DOI：
10.1038/35048589
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发表时间：
2000-12-14
期刊：
影响因子：
64.8
通讯作者：
Edlund, H
中科院分区：
文献类型：
--
作者：
Hart, AW;Baeza, N;Edlund, H
成纤维细胞生长因子（FGF）信号传导与许多器官（包括发育中的胰腺）的模式化、增殖和细胞分化有关（1，2）。在此，我们表明FGF受体（FGFR）1和2，以及配体FGF 1、FGF 2、FGF 4、FGF 5、FGF 7和FGF 10在成年小鼠β细胞中表达，表明FGF信号传导可能在分化的β细胞中起作用.当我们通过在胰腺中表达显性阴性形式的受体FGFR 1c和FGFR 2b来干扰信号传导时，我们发现FGFR 1c信号传导减弱的小鼠，而不是FGFR 2b信号传导减少的小鼠，随着年龄的增长而发展为糖尿病，并表现出β细胞数量的减少，葡萄糖转运蛋白2的表达受损，以及由于激素原转化酶1/3和2的表达受损而导致β细胞中胰岛素原含量增加。这些缺陷都是2型糖尿病患者的特征。同源异型盒基因Ipf 1/Pdx 1的突变与小鼠和人类的糖尿病有关。我们还表明，Ipf 1/Pdx 1是β细胞中FGFR 1信号传导组分表达所必需的，表明Ipf 1/Pdx 1在β细胞中FGFR 1信号传导的上游起作用，以维持适当的葡萄糖感知、胰岛素加工和葡萄糖稳态。
Fibroblast growth factor (FGF) signalling has been implicated in patterning, proliferation and cell differentiation in many organs, including the developing pancreas(1,2). Here we show that the FGF receptors (FGFRs) 1 and 2, together with the ligands FGF1, FGF2, FGF4, FGF5, FGF7 and FGF10, are expressed in adult mouse beta -cells, indicating that FGF signalling may have a role in differentiated beta -cells. When we perturbed signalling by expressing dominant-negative forms of the receptors, FGFR1c and FGFR2b, in the pancreas, we found that that mice with attenuated FGFR1c signalling, but not those with reduced FGFR2b signalling, develop diabetes with age and exhibit a decreased number of beta -cells, impaired expression of glucose transporter 2 and increased proinsulin content in beta -cells owing to impaired expression of prohormone convertases 1/3 and 2. These defects are all characteristic of patients with type-2 diabetes. Mutations in the homeobox gene Ipf1/Pdx1 are linked to diabetes in both mouse and human. We also show that Ipf1/Pdx1 is required for the expression of FGFR1 signalling components in beta -cells, indicating that Ipf1/Pdx1 acts upstream of FGFR1 signalling in beta -cells to maintain proper glucose sensing, insulin processing and glucose homeostasis.