Prompt meningeal reconstruction mediated by oxygen-sensitive AKAP12 scaffolding protein after central nervous system injury

Jong-Ho Cha, Hee-Jun Wee, Ji Hae Seo, Bum Ju Ahn, Ji-Hyeon Park, Jun-Mo Yang, Sae-Won Lee, Ok-Hee Lee, Hyo-Jong Lee, Irwin H. Gelman, Ken Arai, Eng H. Lo and Kyu-Won Kim ()
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Jong-Ho Cha: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University
Hee-Jun Wee: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University
Ji Hae Seo: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University
Bum Ju Ahn: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University
Ji-Hyeon Park: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University
Jun-Mo Yang: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University
Sae-Won Lee: Innovative Research Institute for Cell Therapy, Seoul National University Hospital
Ok-Hee Lee: CHA University
Hyo-Jong Lee: College of Pharmacy, Inje University
Irwin H. Gelman: Roswell Park Cancer Institute
Ken Arai: Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School
Eng H. Lo: Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School
Kyu-Won Kim: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5952

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