Differential, age-dependent MEK-ERK and PI3K-Akt activation by insulin acting as a survival factor during embryonic retinal development
Differential, age-dependent MEK-ERK and PI3K-Akt activation by insulin acting as a survival factor during embryonic retinal development
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DOI：
10.1002/dneu.20554
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发表时间：
2007-11-01
影响因子：
3
通讯作者：
de la Rosa, Enrique J.
中科院分区：
文献类型：
--
作者：
Chavarria, Teresa;Valenciano, Ana I.;de la Rosa, Enrique J.
程序性细胞死亡是神经系统的一个真正的发育过程，不仅影响投射神经元，而且影响增殖的神经上皮细胞和年轻的神经母细胞。鸡胚视网膜已被用于细胞死亡调控的体内和体外相关研究。我们在这里描述了两个主要的信号通路，PI 3 KAkt和MEK-ERK，在胚胎第5天（E5）和E9，当细胞死亡优先影响增殖的神经上皮细胞和神经节细胞神经元，分别控制视网膜器官型培养的作用。在视网膜发育的增殖和早期神经发生阶段（E3-E5），体内程序性细胞死亡的相对密度远高于神经元成熟和突触发生期间（E8-E19）。在来自E5和E9视网膜的器官型培养物中，胰岛素作为唯一添加的生长因子，能够完全防止由生长因子剥夺诱导的细胞死亡。胰岛素激活PI 3 K-Akt和MEK-ERK通路。然而，胰岛素的存活效应在两个阶段被不同地阻断。在E5，该作用被MEK抑制剂阻断，而在E9，其被PI 3 K抑制剂阻断。在E5时发现依赖于MEK-ERK通路的胰岛素活化的细胞主要是增殖的神经上皮细胞。这些观察结果支持了一个显着的特异性，在早期神经细胞死亡的调节。
Programmed cell death is a genuine developmental process of the nervous system, affecting not only projecting neurons but also proliferative neuroepithelial cells and young neuroblasts. The embryonic chick retina has been employed to correlate in vivo and in vitro studies on cell death regulation. We characterize here the role of two major signaling pathways, PI3KAkt and MEK-ERK, in controlled retinal organotypic cultures from embryonic day 5 (E5) and E9, when cell death preferentially affects proliferating neuroepithelial cells and ganglion cell neurons, respectively. The relative density of programmed cell death in vivo was much higher in the proliferative and early neurogenic stages of retinal development (E3-E5) than during neuronal maturation and synaptogenesis (E8-E19). In organotypic cultures from E5 and E9 retinas, insulin, as the only growth factor added, was able to completely prevent cell death induced by growth factor deprivation. Insulin activated both the PI3K-Akt and the MEK-ERK pathways. Insulin survival effect, however, was differentially blocked at the two stages. At E5, the effect was blocked by MEK inhibitors, whereas at E9 it was blocked by PI3K inhibitors. The cells which were found to be dependent on insulin activation of the MEK-ERK pathway at E5 were mostly proliferative neuroepithelial cells. These observations support a remarkable specificity in the regulation of early neural cell death.