Journal
CEREBRAL CORTEX
Volume 26, Issue 5, Pages 2299-2310Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/cercor/bhv292
Keywords
blood-brain barrier; reactive astrogliosis; SOCS3; STAT3; YAP
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Funding
- National Institute of Aging (NIH) [AG045781]
- Department of Veterans Affair [BX000838]
- Natural Science Foundation of Zhejiang Province [LY15C090006]
- Science and Technology Planning Project of Zhejiang Province, China [2013C33167]
- National Natural Science Foundation of China [81371350, 81571190]
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Yes-associated protein (YAP) is a key transcriptional cofactor of the Hippo pathway, critical for the development of multiple organs. However, its role in the developing brain remains poorly understood. Here, we found that YAP was highly expressed in astrocytes and YAP deletion elevated the astrocytic activation in culture and in vivo, which was associated with microglial activation. At the molecular level, YAP in astrocytes was activated by IFN beta or ciliary neurotrophic factor (CNTF), which was necessary for IFN beta or CNTF induction of the suppressor of cytokine signaling 3 (SOCS3), a negative regulator of the Janus kinase-signal transducer and activator of transcription OAK-STAT) inflammatory pathway. YAP(-/-) astrocytes thus showed hyperactivation of the JAK-STAT inflammatory pathway and reactive astrogliosis. Expression of SOCS3 in YAP(-/-) astrocytes prevented the hyperactivation of STAT3 and partially restored the astrocytic activation. Finally, reactive astrogliosis was associated with blood-brain barrier dysfunction in YAP brain-selective knockout mice. Taken together, these results identify unrecognized functions of YAP in preventing reactive astrogliosis and reveal a pathway of YAP-SOCS for the negatively control of neuroinflammation.
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