Injury-independent induction of reactive gliosis in retina by loss of function of the LIM homeodomain transcription factor Lhx2
Injury-independent induction of reactive gliosis in retina by loss of function of the LIM homeodomain transcription factor Lhx2
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DOI：
10.1073/pnas.1107488109
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发表时间：
2012-03-20
影响因子：
11.1
通讯作者：
Blackshaw, Seth
中科院分区：
文献类型：
--
作者：
de Melo, Jimmy;Miki, Katsuaki;Blackshaw, Seth
米勒胶质细胞是视网膜中的主要神经胶质亚型，在支持视网膜功能方面执行多种生理任务，但对于维持这些细胞分化状态的转录网络知之甚少。我们报道，在成熟的米勒胶质细胞中选择性缺失LIM同源结构域转录因子Lhx2会在无损伤的情况下诱导反应性视网膜神经胶质增生。此外，在反应性神经胶质增生开始之前，Prph2(Rd2)/(Rd2)动物中Lhx2的表达也下调。对条件性Lhx2基因敲除的分析表明，神经胶质增生是肥大性的而非增殖性的。对实验动物的老化研究表明，由Lhx2缺失诱导的持续性反应性神经胶质增生降低了正在进行的细胞凋亡率，并损害了视杆和视锥光感受器的功能。此外，这些动物诱导分泌性神经保护因子表达的能力显著降低，并且在光损伤实验中细胞凋亡率增加。我们提供了体内证据，表明Lhx2积极维持成熟的米勒胶质细胞处于非反应性状态，其功能丧失会启动一种特定的非增殖性肥大性神经胶质增生程序。
Muller glia are the primary glial subtype in the retina and perform a wide range of physiological tasks in support of retinal function, but little is known about the transcriptional network that maintains these cells in their differentiated state. We report that selective deletion of the LIM homeodomain transcription factor Lhx2 from mature Muller glia leads to the induction of reactive retinal gliosis in the absence of injury. Furthermore, Lhx2 expression is also down-regulated in Prph2(Rd2)/(Rd2) animals immediately before the onset of reactive gliosis. Analysis of conditional Lhx2 knockouts showed that gliosis was hypertrophic but not proliferative. Aging of experimental animals demonstrated that constitutive reactive gliosis induced by deletion of Lhx2 reduced rates of ongoing apoptosis and compromised both rod and cone photoreceptor function. Additionally, these animals showed a dramatically reduced ability to induce expression of secreted neuroprotective factors and displayed enhanced rates of apoptosis in light-damage assays. We provide in vivo evidence that Lhx2 actively maintains mature Muller glia in a nonreactive state, with loss of function initiating a specific program of nonproliferative hypertrophic gliosis.