A role for ErbB signaling in the induction of reactive astrogliosis.
A role for ErbB signaling in the induction of reactive astrogliosis.
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ErbB 信号传导在诱导反应性星形胶质细胞增生中的作用
DOI：
10.1038/celldisc.2017.44
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发表时间：
2017
期刊：
影响因子：
33.5
通讯作者：
Tao Y
中科院分区：
文献类型：
--
作者：
Chen J;He W;Hu X;Shen Y;Cao J;Wei Z;Luan Y;He L;Jiang F;Tao Y
反应性星形胶质细胞增生是许多神经系统疾病的标志，但其功能和分子机制仍然难以捉摸。特别是，调节星形胶质细胞病理反应的上游信号在很大程度上是不确定的。我们使用小鼠创伤性脑损伤模型诱导星形胶质细胞增生，并揭示了反应性星形胶质细胞中ErbB受体的激活。此外，细胞自主抑制ErbB受体活性的反应性星形胶质细胞的遗传方法抑制肥大性重塑可能通过调节肌动蛋白动力学。然而，抑制反应性星形胶质细胞中的ErbB信号并不影响脑损伤后星形胶质细胞的增殖，尽管它会加重局部炎症。相比之下，小鼠不同脑区成熟星形胶质细胞中的活性ErbB信号传导足以引发反应性反应，再现在受伤或患病大脑中观察到的星形胶质细胞增生的特征性分子和细胞特征。此外，由星形胶质细胞ErbB激活诱导的脑中普遍的星形胶质细胞增生导致动物厌食。因此，我们的研究结果确定了一个未被认识的作用，ErbB信号在诱导反应性星形胶质细胞增生。机制上，抑制ErbB信号在反应性星形胶质细胞显着减少Src和粘着斑激酶（FAK）的活性，这是重要的肌动蛋白重塑，虽然ErbB信号激活多种下游信号蛋白。功能丧失和功能获得研究结果之间的差异表明，ErbB信号通过不同的下游信号通路调节反应性星形胶质细胞的肥大和增殖。我们的工作证明了星形胶质细胞的病理调节的重要机制，并为星形胶质细胞病相关疾病的潜在治疗靶点提供了新的见解。
Reactive astrogliosis is a hallmark of many neurological disorders, yet its functions and molecular mechanisms remain elusive. Particularly, the upstream signaling that regulates pathological responses of astrocytes is largely undetermined. We used a mouse traumatic brain injury model to induce astrogliosis and revealed activation of ErbB receptors in reactive astrocytes. Moreover, cell-autonomous inhibition of ErbB receptor activity in reactive astrocytes by a genetic approach suppressed hypertrophic remodeling possibly through the regulation of actin dynamics. However, inhibiting ErbB signaling in reactive astrocytes did not affect astrocyte proliferation after brain injury, although it aggravated local inflammation. In contrast, active ErbB signaling in mature astrocytes of various brain regions in mice was sufficient to initiate reactive responses, reproducing characterized molecular and cellular features of astrogliosis observed in injured or diseased brains. Further, prevalent astrogliosis in the brain induced by astrocytic ErbB activation caused anorexia in animals. Therefore, our findings defined an unrecognized role of ErbB signaling in inducing reactive astrogliosis. Mechanistically, inhibiting ErbB signaling in reactive astrocytes prominently reduced Src and focal adhesion kinase (FAK) activity that is important for actin remodeling, although ErbB signaling activated multiple downstream signaling proteins. The discrepancies between the results from loss-and gain-of-function studies indicated that ErbB signaling regulated hypertrophy and proliferation of reactive astrocytes by different downstream signaling pathways. Our work demonstrated an essential mechanism in the pathological regulation of astrocytes and provided novel insights into potential therapeutic targets for astrogliosis-implicated diseases.
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DOI：
10.1083/jcb.201508080
发表时间：
2016-02-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Horton ER;Humphries JD;Stutchbury B;Jacquemet G;Ballestrem C;Barry ST;Humphries MJ
通讯作者：
Humphries MJ
DOI：
10.1083/jcb.200504124
发表时间：
2005-11-07
期刊：
The Journal of cell biology
影响因子：
--
作者：
Benlimame N;He Q;Jie S;Xiao D;Xu YJ;Loignon M;Schlaepfer DD;Alaoui-Jamali MA
通讯作者：
Alaoui-Jamali MA
影响因子：
16.2
作者：
Burda JE;Sofroniew MV
通讯作者：
Sofroniew MV
影响因子：
5.3
作者：
Amankulor, Nduka M.;Hambardzumyan, Dolores;Holland, Eric C.
通讯作者：
Holland, Eric C.
影响因子：
11.4
作者：
GrausPorta, D;Beerli, RR;Hynes, NE
通讯作者：
Hynes, NE