CNTF induces photoreceptor neuroprotection and Muller glial cell proliferation through two different signaling pathways in the adult zebrafish retina
CNTF induces photoreceptor neuroprotection and Muller glial cell proliferation through two different signaling pathways in the adult zebrafish retina
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DOI：
10.1016/j.exer.2009.01.007
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发表时间：
2009-06-01
影响因子：
3.4
通讯作者：
Hyde, David R.
中科院分区：
文献类型：
--
作者：
Kassen, Sean C.;Thummel, Ryan;Hyde, David R.
睫状神经营养因子（CNTF）在脊椎动物视网膜中的几个过程中起作用，包括应激的成年视网膜中的光感受器的神经保护和视网膜发育期间神经元祖细胞增殖的调节。然而，它在这些过程中利用的信号通路（Jak/Scat，MAPK或Akt）是不明确的。由于暗适应的白化病斑马鱼表现出光诱导的视杆细胞和视锥细胞死亡，并随后再生失去的感光细胞，斑马鱼应该是一个有用的模型，研究CNTF在神经保护和神经元祖细胞增殖的作用。因此，我们研究了CNTF在未受损和光损伤的成年斑马鱼视网膜中的潜在作用。眼内注射CNTF抑制光诱导的感光细胞死亡，然后未能表现出再生反应，标志着增殖的Muller神经胶质细胞和神经元祖细胞。抑制MAPK信号通路，而不是Stat 3或Akt通路，显着降低CNTF介导的光诱导的感光细胞死亡的神经保护。眼内注射CNTF到非光处理（未受损）的眼睛模仿恒定的强光治疗，增加Stat 3的表达，然后增加增殖的Muller神经胶质细胞和神经元祖细胞的数量。在CNTF注射的非光处理的视网膜中Stat 3表达的敲低显著减少了增殖的Muller胶质细胞的数量，而CNTF与MAPK或Akt抑制剂的共注射没有抑制CNTF诱导的Muller胶质细胞增殖。因此，CNTF利用MAPK依赖性信号通路在光诱导的感光细胞死亡的神经保护和Stat 3依赖性信号通路刺激Muller神经胶质细胞增殖。(C)2009爱思唯尔有限公司保留所有权利。
Ciliary neurotrophic factor (CNTF) acts in several processes in the vertebrate retina, including neuroprotection of photoreceptors in the stressed adult retina and regulation of neuronal progenitor cell proliferation during retinal development. However, the signaling pathway it utilizes (Jak/Scat, MAPK, or Akt) in these processes is ambiguous. Because dark-adapted albino zebrafish exhibit light-induced rod and cone cell death and subsequently regenerate the lost photoreceptor cells, zebrafish should be a useful model to study the role of CNTF in both neuroprotection and neuronal progenitor cell proliferation. We therefore investigated the potential roles of CNTF in both the undamaged and light-damaged adult zebrafish retinas. Intraocular injection of CNTF suppressed light-induced photoreceptor cell death, which then failed to exhibit the regeneration response that is marked by proliferating Muller glia and neuronal progenitor cells. Inhibiting the MAPK signaling pathway, but neither the Stat3 nor Akt pathways, significantly reduced the CNTF-mediated neuroprotection of light-induced photoreceptor cell death. Intraocular injection of CNTF into non-light-treated (undamaged) eyes mimicked constant intense light treatment by increasing Stat3 expression in Muller glia followed by increasing the number of proliferating Muller glia and neuronal progenitors. Knockdown of Stat3 expression in the CNTF-injected non-light-treated retinas significantly reduced the number of proliferating Muller glia, while coinjection of CNTF with either MAPK or Akt inhibitors did not inhibit the CNTF-induced Muller glia proliferation. Thus, CNTF utilizes a MAPK-dependant signaling pathway in neuroprotection of light-induced photoreceptor cell death and a Stat3-dependant signaling pathway to stimulate Muller glia proliferation. (C) 2009 Elsevier Ltd. All rights reserved.