Early downregulation of IGF-I decides the fate of rat retinal ganglion cells after optic nerve injury
Early downregulation of IGF-I decides the fate of rat retinal ganglion cells after optic nerve injury
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DOI：
10.1016/j.neuint.2007.01.011
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发表时间：
2007-04-01
影响因子：
4.2
通讯作者：
Kato, Satoru
中科院分区：
文献类型：
--
作者：
Homma, Keiko;Koriyama, Yoshiki;Kato, Satoru
视神经损伤后，视网膜神经节细胞（RGCs）通过凋亡而死亡。许多报道分别显示了视神经损伤后促凋亡蛋白如Bcl-2家族成员的变化。然而，这些凋亡信号的诱导时间尚未确定，由于视神经的不同治疗，以及测量的时间间隔不足。因此，细胞死亡信号流还没有得到很好的理解。在本研究中，我们系统地重新研究了这些细胞死亡/存活信号在大鼠视网膜视神经挤压后的详细时间过程，以确定导致RGC凋亡的信号级联。在视网膜中检测到的最显著的变化是视神经损伤后2-3天磷酸化Akt和磷酸化Bad蛋白的快速失活，以及随后的Bax蛋白和caspase-3活性的逐渐激活，伴随着神经损伤后6天的RGCs细胞损失。这些分子变化的细胞定位仅限于RGC。此外，胰岛素样生长因子-I（IGF-I）（磷脂酰肌醇-3-激酶（PI 3 K）/Akt系统的激活剂）的量在磷酸化Akt通过视神经挤压失活之前1-2天从RGC开始减少。相反，在大鼠视网膜中补充IGF-I诱导了磷酸化Akt表达的上调和体外和体内RGC细胞的存活。因此，视神经损伤可能会导致细胞内稳态的早期变化，并可能失去对受损RGC的营养支持。事实上，IGF-I通过渥曼青霉素依赖性机制在视网膜外植体培养中显著增强了成年大鼠RGCs的神经突生长。我们的数据有力地表明，IGF-I是在视神经损伤的早期诱导视网膜RGC凋亡或RGC存活和再生的关键分子。(c)2007爱思唯尔有限公司保留所有权利。
Retinal ganglion cells (RGCs) die by apoptosis after optic nerve injury. A number of reports have separately shown changes in pro-apoptotic proteins such as the Bcl-2 family members following optic nerve injury. However, induction time of these apoptotic signals has not been identified due to different treatments of the optic nerve, and insufficient time intervals for measurements. Therefore, the stream of cell death signals is not well understood. In the present study, we systematically reinvestigated a detailed time course of these cell death/survival signals in the rat retina after optic nerve crush, to determine the signal cascade leading to RGC apoptosis. The most conspicuous changes detected in the retina were the rapid inactivation of phospho-Akt and phospho-Bad proteins 2-3 days after optic nerve damage, and the subsequent gradual activation of Bax protein and caspase-3 activity accompanied by cell loss of RGCs 6 days after nerve injury. Cellular localization of these molecular changes was limited to RGCs. Furthermore, amount of insulin-like growth factor-I (IGF-I), an activator of the phosphatidyl inositol-3-kinase (PI3K)/Akt system, was initially decreased from RGCs 1-2 days just prior to the inactivation of phospho-Akt by optic nerve crush. Conversely, supplementation with IGF-I into the rat retina induced upregulation of phospho-Akt expression and cell survival of RGCs both in vitro and in vivo. Thus, injury to the optic nerve might induce early changes in cellular homeostasis with a plausible loss of trophic support for injured RGCs. Actually, IGF-I drastically enhanced neurite outgrowth from adult rat RGCs via a wortmannin-dependent mechanism in a retinal explant culture. Our data strongly indicate that IGF-I is a key molecule that induces RGC apoptosis or RGC survival and regeneration in the retina during the early stage of optic nerve injury. (c) 2007 Elsevier Ltd. All rights reserved.