title: Prompt meningeal reconstruction mediated by oxygen-sensitive AKAP12 scaffolding protein after central nervous system injury.
abstract: The meninges forms a critical epithelial barrier, which protects the central nervous system (CNS), and therefore its prompt reconstruction after CNS injury is essential for reducing neuronal damage. Meningeal cells migrate into the lesion site after undergoing an epithelial-mesenchymal transition (EMT) and repair the impaired meninges. However, the molecular mechanisms of meningeal EMT remain largely undefined. Here we show that TGF-β1 and retinoic acid (RA) released from the meninges, together with oxygen tension, could constitute the mechanism for rapid meningeal reconstruction. AKAP12 is an effector of this mechanism, and its expression in meningeal cells is regulated by integrated upstream signals composed of TGF-β1, RA and oxygen tension. Functionally, AKAP12 modulates meningeal EMT by regulating the TGF-β1-non-Smad-SNAI1 signalling pathway. Collectively, TGF-β1, RA and oxygen tension can modulate the dynamic change in AKAP12 expression, causing prompt meningeal reconstruction after CNS injury by regulating the transition between the epithelial and mesenchymal states of meningeal cells.
authors.affiliation: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Jong-Ho
authors.initials: JH
authors.lastname: Cha
authors.affiliation: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Hee-Jun
authors.initials: HJ
authors.lastname: Wee
authors.affiliation: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Ji Hae
authors.initials: JH
authors.lastname: Seo
authors.affiliation: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Bum Ju
authors.initials: BJ
authors.lastname: Ahn
authors.affiliation: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Ji-Hyeon
authors.initials: JH
authors.lastname: Park
authors.affiliation: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Jun-Mo
authors.initials: JM
authors.lastname: Yang
authors.affiliation: Department of Internal Medicine, Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul 110-799, Korea.
authors.forename: Sae-Won
authors.initials: SW
authors.lastname: Lee
authors.affiliation: Department of Biomedical Science, CHA University, Seoul 135-081, Korea.
authors.forename: Ok-Hee
authors.initials: OH
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Inje University, Gimhae 621-749, Korea.
authors.forename: Hyo-Jong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
authors.forename: Irwin H
authors.initials: IH
authors.lastname: Gelman
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Arai
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, USA.
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
authors.affiliation: 1] SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea [2] Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Kyu-Won
authors.initials: KW
authors.lastname: Kim
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism*; D000818:Animals; D001099:Arachnoid / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002490:Central Nervous System / Q000293:injuries*; D004847:Epithelial Cells / Q000166:cytology; D058750:Epithelial-Mesenchymal Transition; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008578:Meninges / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D010100:Oxygen / Q000737:chemistry*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000166:cytology; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism
chemical_list: D054758:A Kinase Anchor Proteins; C491162:AKAP12 protein, human; C491161:Akap12 protein, mouse; D018797:Cell Cycle Proteins; D018168:Receptors, Retinoic Acid; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C082925:retinoic acid receptor beta; D014212:Tretinoin; D010100:Oxygen