Nuclear factor I-A regulates diverse reactive astrocyte responses after CNS injury
Nuclear factor I-A regulates diverse reactive astrocyte responses after CNS injury
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DOI：
10.1172/jci127492
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发表时间：
2019-10-01
影响因子：
15.9
通讯作者：
Deneen, Benjamin
中科院分区：
文献类型：
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作者：
Laug, Dylan;Huang, Teng-Wei;Deneen, Benjamin
反应性星形胶质细胞与各种形式的神经损伤有关。尽管它们无处不在，但控制其产生和多种功能的分子机制仍不清楚。由于星形胶质细胞发育的许多特征在反应性星形胶质细胞中重现，我们研究了核因子I-A （NFIA）的作用，这是星形胶质细胞发育的关键转录调节因子，其对反应性星形胶质细胞的贡献尚不清楚。在这里，我们发现NFIA在人类神经损伤的反应性星形胶质细胞中高度表达，并在不同的损伤状态和中枢神经系统区域中确定了独特的作用。在脊髓中，白质损伤（WMI）后，缺乏nfia的星形胶质细胞在血脑屏障重构中表现出缺陷，这与及时髓鞘再生受到抑制有关。在脑皮质，缺血性卒中后，NFIA是脑室下区（SVZ）产生反应性星形胶质细胞所必需的。在机制上，NFIA直接调节SVZ中血栓反应蛋白4 （Thbs4）的表达，揭示了一个调节反应性星形胶质细胞发生的关键转录节点。总之，这些研究揭示了NFIA在反应性星形胶质细胞中的关键作用，并说明了区域和损伤特异性因素如何决定反应性星形胶质细胞反应的光谱。
Reactive astrocytes are associated with every form of neurological injury. Despite their ubiquity, the molecular mechanisms controlling their production and diverse functions remain poorly defined. Because many features of astrocyte development are recapitulated in reactive astrocytes, we investigated the role of nuclear factor I-A (NFIA), a key transcriptional regulator of astrocyte development whose contributions to reactive astrocytes remain undefined. Here, we show that NFIA is highly expressed in reactive astrocytes in human neurological injury and identify unique roles across distinct injury states and regions of the CNS. In the spinal cord, after white matter injury (WMI), NFIA-deficient astrocytes exhibit defects in blood-brain barrier remodeling, which are correlated with the suppression of timely remyelination. In the cortex, after ischemic stroke, NFIA is required for the production of reactive astrocytes from the subventricular zone (SVZ). Mechanistically, NFIA directly regulates the expression of thrombospondin 4 (Thbs4) in the SVZ, revealing a key transcriptional node regulating reactive astrogenesis. Together, these studies uncover critical roles for NFIA in reactive astrocytes and illustrate how region-and injury-specific factors dictate the spectrum of reactive astrocyte responses.