气候变化领域集成服务门户(CCPortal): Inactivation of Hedgehog signal transduction in adult astrocytes results in region-specific blood

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DOI	10.1073/pnas.2017779118
	Inactivation of Hedgehog signal transduction in adult astrocytes results in region-specific blood–brain barrier defects
	Wang H.; Xu Z.; Xia Z.; Rallo M.; Duffy A.; Matise M.P.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:34
英文摘要	In this study, we use molecular genetic approaches to clarify the role of the Hedgehog (Hh) pathway in regulating the blood–brain/spinal cord barrier (BBB) in the adult mouse central nervous system (CNS). Our work confirms and extends prior studies to demonstrate that astrocytes are the predominant cell type in the adult CNS that transduce Hh signaling, revealed by the expression of Gli1, a target gene of the canonical pathway that is activated in cells receiving Hh, and other key pathway transduction components. Gli1+ (Hh-responsive) astrocytes are distributed in specific regions of the CNS parenchyma, including layers 4/5/6 of the neocortex, hypothalamus, thalamus, and spinal cord, among others. Notably, although BBB properties in endothelial cells are normally regulated by both paracellular and transcellular mechanisms, conditional inactivation of Hh signaling in astrocytes results in transient, region-specific BBB defects that affect transcytosis but not paracellular diffusion. These findings stand in contrast to prior studies that implicated astrocytes as a source of Sonic hedgehog that limited extravasation via both mechanisms [J. I. Alvarez et al., Science 334, 1727–1731 (2011)]. Furthermore, using three distinct Cre driver lines as well as pharmacological approaches to inactivate Hh-pathway transduction globally in CNS astrocytes, we find that these specific BBB defects are only detected in the rostral hypothalamus and spinal cord but not the cortex or other regions where Gli1+ astrocytes are found. Together, our data show that Gli1+ Hh-responsive astrocytes have regionally distinct molecular and functional properties and that the pathway is required to maintain BBB properties in specific regions of the adult mammalian CNS. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Albumin extravasation; Astrocyte; Blood–brain barrier; Sonic hedgehog; Transcytosis
语种	英语
scopus关键词	cyclopamine; selective estrogen receptor modulator; Smo protein, mouse; Smoothened protein; sonic hedgehog protein; tamoxifen; Veratrum alkaloid; animal; astrocyte; blood brain barrier; brain; drug effect; gene expression regulation; genetics; gliosis; metabolism; mouse; spinal cord; transgenic mouse; Animals; Astrocytes; Blood-Brain Barrier; Brain; Gene Expression Regulation; Gliosis; Hedgehog Proteins; Mice; Mice, Transgenic; Selective Estrogen Receptor Modulators; Smoothened Receptor; Spinal Cord; Tamoxifen; Veratrum Alkaloids
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251039
作者单位	Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, 226001, China; Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers Biomedical and Health Sciences, Piscataway, NJ 08854, United States
推荐引用方式 GB/T 7714	Wang H.,Xu Z.,Xia Z.,等. Inactivation of Hedgehog signal transduction in adult astrocytes results in region-specific blood–brain barrier defects[J],2021,118(34).
APA	Wang H.,Xu Z.,Xia Z.,Rallo M.,Duffy A.,&Matise M.P..(2021).Inactivation of Hedgehog signal transduction in adult astrocytes results in region-specific blood–brain barrier defects.Proceedings of the National Academy of Sciences of the United States of America,118(34).
MLA	Wang H.,et al."Inactivation of Hedgehog signal transduction in adult astrocytes results in region-specific blood–brain barrier defects".Proceedings of the National Academy of Sciences of the United States of America 118.34(2021).