MiRNA-132/212 regulates tight junction stabilization in blood–brain barrier after stroke

MicroRNA-132/212 has been supposed as a critical gene related to the blood–brain barrier (BBB) protection after stroke, but its regulation pathway including the upstream regulator and downstream targets is still unclear. Herein, we demonstrated the cAMP response element-binding protein (CREB)-regula...

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Bibliographic Details
Published in:Cell death discovery 2021-12, Vol.7 (1), p.380-380, Article 380
Main Authors: Yan, Haomin, Kanki, Hideaki, Matsumura, Shigenobu, Kawano, Tomohiro, Nishiyama, Kumiko, Sugiyama, Shintaro, Takemori, Hiroshi, Mochizuki, Hideki, Sasaki, Tsutomu
Format: Article
Language:English
Subjects:
3' Untranslated regions
631/378/1341
631/378/2607
Apoptosis
Biochemistry
Biomedical and Life Sciences
Blood-brain barrier
Cell Biology
Cell culture
Cell Cycle Analysis
Cyclic AMP response element-binding protein
Endothelial cells
Gene therapy
Hypoxia
Ischemia
Life Sciences
Membrane permeability
MicroRNAs
miRNA
Neurological diseases
Permeability
Stem Cells
Stroke
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Summary:MicroRNA-132/212 has been supposed as a critical gene related to the blood–brain barrier (BBB) protection after stroke, but its regulation pathway including the upstream regulator and downstream targets is still unclear. Herein, we demonstrated the cAMP response element-binding protein (CREB)-regulated transcription coactivator-1 (CRTC1) to be the upstream regulator of miRNA-132/212 using CRTC1 knockout and wild-type mice. CRTC1 deletion led to the reduction of miRNA-132/212 expression in mice brain after ischemic stroke, significantly increased infarct volume, and aggravated BBB permeability with worsening neurological deficits. Furthermore, we identified that miRNA-132 repressed Claudin-1, tight junction-associated protein-1 (TJAP-1), and RNA-binding Fox-1 (RBFox-1) by directly binding to their respective 3′-untranslated regions, which alleviated the ischemic damage by enhancing neuronal survival and BBB integrity. Moreover, the co-culture of endothelial cells with CRTC1-deficient neurons aggravated the cell vulnerability to hypoxia, also supporting the idea that miRNA-132/212 cluster is regulated by CRTC1 and acts as a crucial role in the mitigation of ischemic damage. This work is a step forward for understanding the role of miRNA-132/212 in neurovascular interaction and may be helpful for potential gene therapy of ischemic stroke.
ISSN:2058-7716
2058-7716
DOI:10.1038/s41420-021-00773-w