Tumor necrosis factor-alpha is produced by dying retinal neurons and is required for Muller glia proliferation during zebrafish retinal regeneration.
Tumor necrosis factor-alpha is produced by dying retinal neurons and is required for Muller glia proliferation during zebrafish retinal regeneration.
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DOI：
10.1523/jneurosci.3838-12.2013
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发表时间：
2013-04-10
期刊：
影响因子：
--
通讯作者：
Hyde DR
中科院分区：
文献类型：
--
作者：
Nelson CM;Ackerman KM;O'Hayer P;Bailey TJ;Gorsuch RA;Hyde DR
强光照射导致暗适应的成年白化斑马鱼(Danio Rerio)感光细胞凋亡。随后，Müller胶质细胞增加Achaete-scute Complex-like 1a(Ascl1a)和信号转导和转录激活因子3(STAT3)转录因子的表达，重新进入细胞周期，产生未分化的神经元前体细胞，继续增殖，迁移到外核层，并分化为光感受器。对光损伤的视网膜匀浆进行的蛋白质组学分析显示，与未受损的视网膜匀浆相比，肿瘤坏死因子α(肿瘤坏死因子α)信号蛋白的表达增加。肿瘤坏死因子α最初在凋亡的光感受器中表达增加，后来在Müler神经胶质细胞中表达增加。吗啡介导的肿瘤坏死因子α在光损伤前的表达下调减少了Müler胶质细胞中Ascl1a和STAT3的表达，并显著减少了增殖的Müler胶质细胞的数量，但不影响光感受器细胞的死亡。抑制Müler神经胶质细胞中肿瘤坏死因子α的表达，导致增殖的Müler神经胶质细胞减少，提示Müler神经胶质来源的肿瘤坏死因子α招募更多的Müler神经胶质细胞重新进入细胞周期。肿瘤坏死因子α是上调Ascl1a和STAT3表达所必需的，而Ascl1a和STAT3是Müler胶质细胞表达肿瘤坏死因子α所必需的。玻璃体内注射哇巴因引起的视网膜内神经元凋亡，也表现出Müler胶质细胞增殖所必需的肿瘤坏死因子α的表达增加。因此，肿瘤坏死因子α是第一个被鉴定的分子，它是由死亡的视网膜神经元产生的，在斑马鱼的视网膜再生反应中诱导Müler胶质细胞增殖是必要的。
Intense light exposure causes photoreceptor apoptosis in dark-adapted adult albino zebrafish (Danio rerio). Subsequently, Müller glia increase expression of the Achaete-scute complex-like 1a (Ascl1a) and Signal transducer and activator of transcription 3(Stat3) transcription factors and reenter the cell cycle to yield undifferentiated neuronal progenitors that continue to proliferate, migrate to the outer nuclear layer, and differentiate into photoreceptors. A proteomic analysis of light-damaged retinal homogenates, which induced Müller glia proliferation when injected into an undamaged eye, revealed increased expression of Tumor necrosis factor α (TNFα) signaling proteins relative to undamaged retinal homogenates. TNFα expression initially increased in apoptotic photoreceptors and later in Müller glia. Morpholino-mediated knockdown of TNFα expression prior to light damage diminished the expression of both Ascl1a and Stat3 in Müller glia and significantly reduced the number of proliferating Müller glia without affecting photoreceptor cell death. Knockdown of TNFα expression in the Müller glia resulted in fewer proliferating Müller glia, suggesting that Müller glial-derived TNFα recruited additional Müller glia to reenter the cell cycle. While TNFα is required for increased Ascl1a and Stat3 expression, Ascl1a and Stat3 are both necessary for TNFα expression in Müller glia. Apoptotic inner retinal neurons, resulting from intravitreal injection of ouabain, also exhibited increased TNFα expression that was required for Müller glia proliferation. Thus, TNFα is the first molecule identified that is produced by dying retinal neurons and is necessary to induce Müller glia to proliferate in the zebrafish retinal regeneration response.