@article{3ba4690ec6d24abd959c4a512ff76438,
title = "Disruption of Bmal1 impairs blood-brain barrier integrity via pericyte dysfunction",
abstract = "Circadian rhythm disturbances are well established in neurological diseases. However, how these disruptions cause homeostatic imbalances remains poorly understood. Brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1) is a major circadian clock transcriptional activator, and Bmal1 deficiency in male Bmal1nestin+/+ mice induced marked astroglial activation without affecting the number of astrocytes in the brain and spinal cord. Bmal1 deletion caused blood-brain barrier (BBB) hyperpermeability with an age-dependent loss of pericyte coverage of blood vessels in the brain. Using Nestin-green fluorescent protein(GFP) transgenic mice, we determined that pericytes are Nestin-GFP+ in the adult brain. Bmal1 deletion caused Nestin-GFP+ pericyte dysfunction, including the downregulation of platelet-derived growth factor receptor β (PDGFRβ), a protein necessary for maintaining BBB integrity. Knockdown of Bmal1 downregulated PDGFRβ transcription in the brain pericyte cell line. Thus, the circadian clock component Bmal1 maintains BBB integrity via regulating pericytes.",
keywords = "Blood-brain barrier, Clock gene, Pericyte",
author = "Ryota Nakazato and Kenji Kawabe and Daisuke Yamada and Shinsuke Ikeno and Michihiro Mieda and Shigeki Shimba and Eiichi Hinoi and Yukio Yoneda and Takeshi Takarada",
note = "Funding Information: Received Nov. 26, 2016; revised Sept. 4, 2017; accepted Sept. 7, 2017. Author contributions: K.K., D.Y., E.H., Y.Y., and T.T. designed research; R.N., K.K., and S.I. performed research; M.M.andS.S.contributedunpublishedreagents/analytictools;R.N.andS.I.analyzeddata;R.N.,K.K.,D.Y.,andT.T. wrote the paper. This work was supported in part by Grants-in-Aid for Scientific Research on Innovative Areas (26117507 and 16H01332)andforScientificResearchonInnovativeAreas(ComprehensiveBrainScienceNetwork)toT.T.fromthe MinistryofEducation,Culture,Sports,ScienceandTechnology,Japan;andinpartbyaresearchgranttoT.T.fromthe Nakatomi Foundation. We thank Dr. G. Enikolopov (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY), Dr. Jamey D. Marth (University of California, Santa Barbara, Santa Barbara, CA), and Dr. Shigeyoshi Itohara (RIKEN Brain Science Institute, Saitama, Japan) for generously providing the Nestin-GFP, Synapsin I-Cre, and S100β-Cre mice, respectively. The authors declare no competing financial interests. Correspondence should be addressed to Takeshi Takarada, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. E-mail: takarada@okayama-u.ac.jp. DOI:10.1523/JNEUROSCI.3639-16.2017 Copyright {\textcopyright} 2017 the authors 0270-6474/17/3710052-11$15.00/0",
year = "2017",
month = oct,
day = "18",
doi = "10.1523/JNEUROSCI.3639-16.2017",
language = "English",
volume = "37",
pages = "10052--10062",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "42",
}