Transgenic activation of Ras in neurons promotes hypertrophy and protects from lesion-induced degeneration.
Transgenic activation of Ras in neurons promotes hypertrophy and protects from lesion-induced degeneration.
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DOI：
10.1083/jcb.151.7.1537
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发表时间：
2000-12-25
影响因子：
7.8
通讯作者：
Berns, H
中科院分区：
文献类型：
--
作者：
Heumann, R;Goemans, C;Bartsch, D;Lingenhohl, K;Waldmeier, P C;Hengerer, B;Allegrini, P R;Schellander, K;Wagner, E F;Arendt, T;Kamdem, R H;Obst-Pernberg, K;Narz, F;Wahle, P;Berns, H
Ras是一种整合多种受体类型胞外信号的通用真核细胞内蛋白。为了研究其在成年中枢神经系统中的作用，通过突触蛋白启动子在转基因小鼠的神经元中选择性地表达组成型激活的V12-Ha-Ras。Ras转基因蛋白表达在出生后增加，在第40天达到4 - 5倍的升高，此后持续在这个水平。神经元Ras是组成性活性和相应的有丝分裂原活化激酶的活化磷酸化观察，但有没有变化的活性磷酸肌醇3-激酶，其靶激酶Akt/PKB的磷酸化，或表达的抗凋亡蛋白Bcl-2或Bcl-XL。神经元Ras激活不改变神经元总数，但诱导细胞索马肥大，导致总脑体积增加14.5%。胆碱乙酰转移酶和酪氨酸羟化酶活性增加，神经肽Y表达也增加。Ras转基因小鼠面神经损伤后，运动神经元的变性被完全阻止。此外，神经毒素诱导的黑质多巴胺能神经元及其纹状体投射的变性大大减弱。因此，Ras信号通路模拟成年小鼠的神经营养作用并触发神经保护机制。神经元Ras激活可能成为稳定神经移植供体神经元和保护神经退行性疾病中神经元群体的工具。
Ras is a universal eukaryotic intracellular protein integrating extracellular signals from multiple receptor types. To investigate its role in the adult central nervous system, constitutively activated V12-Ha-Ras was expressed selectively in neurons of transgenic mice via a synapsin promoter. Ras-transgene protein expression increased postnatally, reaching a four- to fivefold elevation at day 40 and persisting at this level, thereafter. Neuronal Ras was constitutively active and a corresponding activating phosphorylation of mitogen-activated kinase was observed, but there were no changes in the activity of phosphoinositide 3-kinase, the phosphorylation of its target kinase Akt/PKB, or expression of the anti-apoptotic proteins Bcl-2 or Bcl-XL. Neuronal Ras activation did not alter the total number of neurons, but induced cell soma hypertrophy, which resulted in a 14.5% increase of total brain volume. Choline acetyltransferase and tyrosine hydroxylase activities were increased, as well as neuropeptide Y expression. Degeneration of motorneurons was completely prevented after facial nerve lesion in Ras-transgenic mice. Furthermore, neurotoxin-induced degeneration of dopaminergic substantia nigra neurons and their striatal projections was greatly attenuated. Thus, the Ras signaling pathway mimics neurotrophic effects and triggers neuroprotective mechanisms in adult mice. Neuronal Ras activation might become a tool to stabilize donor neurons for neural transplantation and to protect neuronal populations in neurodegenerative diseases.