Ciliary Neurotrophic Factor and Stress Stimuli Activate the Jak-STAT Pathway in Retinal Neurons and Glia
Ciliary Neurotrophic Factor and Stress Stimuli Activate the Jak-STAT Pathway in Retinal Neurons and Glia
复制标题
DOI：
10.1523/jneurosci.20-11-04081.2000
复制
发表时间：
2000-06
期刊：
影响因子：
--
通讯作者：
W. Peterson;Quan Wang;Roumiana Tzekova;S. Wiegand
中科院分区：
文献类型：
--
作者：
W. Peterson;Quan Wang;Roumiana Tzekova;S. Wiegand
睫状神经营养因子（CNTF）对中枢、外周和感觉神经元具有多效性。在成熟的视网膜中，CNTF处理增强了暴露于其他致命扰动的视网膜神经节和感光细胞的存活。为了解CNTF在体内的作用机制，以成年大鼠视网膜为模型，研究CNTF对Janus激酶/信号转导子和转录激活子（Jak-STAT）和ras-丝裂原活化蛋白激酶（ras-MAPK）的激活作用。玻璃体内注射CNTF类似物Axokine，磷酸化STAT 3和MAPK，并在大鼠视网膜中产生总STAT 3和STAT 1蛋白的延迟上调。活化的STAT 3主要定位于视网膜Müller（神经胶质）细胞、神经节细胞和星形胶质细胞的核中，但不在光感受器中。尽管CNTF α受体（CNTFRα）mRNA和蛋白主要定位于视网膜神经元，但在神经胶质细胞和神经元中均观察到了CNTF介导的STAT 3信号传导。CNTF诱导的Jak-STAT信号的激活促使我们在各种应激介导的条件刺激后研究STAT 3的磷酸化。我们发现，STAT 3在暴露于亚毒性强光、机械创伤和全身给予α2-肾上腺素能激动剂甲苯噻嗪后在视网膜中被激活，所有这些都已被证明可以调节光感受器以抵抗光诱导的变性。这些结果表明，CNTF直接刺激Jak-STAT和ras-MAPK级联反应在体内，并强烈表明，STAT 3信号是一个潜在的组成部分，神经反应的压力刺激。CNTF在神经节细胞中激活STAT 3，但在光感受器中不激活STAT 3的观察结果表明，Jak-STAT信号通过直接和间接的作用模式影响神经元的存活。
Ciliary neurotrophic factor (CNTF) is pleiotrophic for central, peripheral, and sensory neurons. In the mature retina, CNTF treatment enhances survival of retinal ganglion and photoreceptor cells exposed to otherwise lethal perturbation. To understand its mechanism of actionin vivo, the adult rat retina was used as a model to investigate CNTF-mediated activation of Janus kinase/signal transducer and activator of transcription (Jak-STAT) and ras-mitogen activated protein kinase (ras-MAPK). Intravitreal injection of Axokine, an analog of CNTF, phosphorylates STAT3 and MAPK and produces delayed upregulation of total STAT3 and STAT1 protein in rat retina. Activated STAT3 is predominantly localized in nuclei of retinal Müller (glial) cells, ganglion cells, and astrocytes, but not in photoreceptors. Although CNTF α-receptor (CNTFRα) mRNA and protein are localized predominantly if not exclusively in retinal neurons, coincident CNTF-mediated STAT3 signaling was observed in both glia and neurons. CNTF-induced activation of Jak-STAT signaling prompted us to investigate STAT3 phosphorylation after a variety of stress-mediated, conditioning stimuli. We show that STAT3 is activated in the retina after exposure to subtoxic bright light, mechanical trauma, and systemic administration of the α2-adrenergic agonist xylazine, all of which have been shown previously to condition photoreceptors to resist light-induced degeneration. These results demonstrate that CNTF directly stimulates Jak-STAT and ras-MAPK cascades in vivo and strongly suggest that STAT3 signaling is an underlying component of neural responsiveness to stress stimuli. The observation that CNTF activates STAT3 in ganglion cells, but not in photoreceptors, suggests that Jak-STAT signaling influences neuronal survival via both direct and indirect modes of action.