期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：28
页码：8726-8731
DOI：10.1073/pnas.1501029112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceWe demonstrate a signaling axis that controls reactive astrogliosis after brain injury based on the Notch1 receptor, signal transducer and activator of transcription 3 (STAT3), and endothelin receptor type B (ETBR). Knowledge of the Notch1-STAT3-ETBR signaling axis provides fundamental insight into the signaling network that regulates reactive astrocyte proliferation after brain injury. In addition, we identify the first set of markers for prospective isolation of proliferative reactive astrocytes directly from injured CNS tissue (GLAST+/Jagged1Hi) and describe a unique method to generate large quantities of primary adult reactive astrocytes based on redifferentiation from reactive astrocyte-derived neural stem cells. These tools provide a powerful platform to map the signaling network that controls reactive astrogliosis. Defining the signaling network that controls reactive astrogliosis may provide novel treatment targets for patients with diverse CNS injuries and pathologies. We report that the radial glial cell antigen RC2 identifies the majority of proliferating glial fibrillary acidic protein-positive (GFAP+) reactive astrocytes after stroke. These cells highly expressed endothelin receptor type B (ETBR) and Jagged1, a Notch1 receptor ligand. To study signaling in adult reactive astrocytes, we developed a model based on reactive astrocyte-derived neural stem cells isolated from GFAP-CreER-Notch1 conditional knockout (cKO) mice. By loss- and gain-of-function studies and promoter activity assays, we found that Jagged1/Notch1 signaling increased ETBR expression indirectly by raising the level of phosphorylated signal transducer and activator of transcription 3 (STAT3), a previously unidentified EDNRB transcriptional activator. Similar to inducible transgenic GFAP-CreER-Notch1-cKO mice, GFAP-CreER-ETBR-cKO mice exhibited a defect in reactive astrocyte proliferation after cerebral ischemia. Our results indicate that the Notch1-STAT3-ETBR axis connects a signaling network that promotes reactive astrocyte proliferation after brain injury.
