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Published on: July 14, 2016
MicroRNA-200c contributes to injury from transient focal cerebral ischemia by targeting Reelin
Creed M Stary1, Lijun Xu1, Xiaoyun Sun1
1From the Department of Anesthesia, Stanford University School of Medicine, CA (C.M.S, L.X., X.S., Y.-B.O., J. Leong, J. Li, X.X., R.G.G.); and Department of Biology, Westfield State University, MA (R.E.W.).
Background And Purpose:
MicroRNA (miR)-200c increases rapidly in the brain after transient cerebral ischemia but its role in poststroke brain injury is unclear. Reelin, a regulator of neuronal migration and synaptogenesis, is a predicted target of miR-200c. We hypothesized that miR-200c contributes to injury from transient cerebral ischemia by targeting reelin.
Methods:
Brain infarct volume, neurological score and levels of miR-200c, reelin mRNA, and reelin protein were assessed in mice subjected to 1 hour of middle cerebral artery occlusion with or without intracerebroventricular infusion of miR-200c antagomir, mimic, or mismatch control. Direct targeting of reelin by miR-200c was assessed in vitro by dual luciferase assay and immunoblot.
Results:
Pretreatment with miR-200c antagomir decreased post-middle cerebral artery occlusion brain levels of miR-200c, resulting in a significant reduction in infarct volume and neurological deficit. Changes in brain levels of miR-200c inversely correlated with reelin protein expression. Direct targeting of the Reln 3' untranslated region by miR-200c was verified with dual luciferase assay. Inhibition of miR-200c resulted in an increase in cell survival subsequent to in vitro oxidative injury. This effect was blocked by knockdown of reelin mRNA, whereas application of reelin protein afforded protection.
Conclusions:
These findings suggest that the poststroke increase in miR-200c contributes to brain cell death by inhibiting reelin expression, and that reducing poststroke miR-200c is a potential target to mitigate stroke-induced brain injury.
Insights
MicroRNA-200c inhibition reduces brain damage after stroke by increasing reelin expression. This finding suggests targeting microRNA-200c may protect against stroke-induced brain injury.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- MicroRNA (miR)-200c levels rise in the brain post-ischemia.
- The role of miR-200c in stroke-related brain injury is not fully understood.
- Reelin, a key protein in neuronal development, is a predicted target of miR-200c.
Purpose of the Study:
- To investigate the role of miR-200c in transient cerebral ischemia.
- To determine if miR-200c contributes to stroke-induced brain injury by targeting reelin.
Main Methods:
- Mice underwent middle cerebral artery occlusion (MCAO) with miR-200c antagomir, mimic, or control infusion.
- Infarct volume, neurological scores, and molecular levels (miR-200c, reelin mRNA/protein) were measured.
- In vitro assays (dual luciferase, immunoblot) confirmed direct targeting of reelin by miR-200c.
Main Results:
- miR-200c antagomir treatment reduced infarct volume and neurological deficits post-MCAO.
- miR-200c levels inversely correlated with reelin protein expression.
- Inhibition of miR-200c enhanced cell survival during oxidative injury, an effect dependent on reelin.
Conclusions:
- Poststroke miR-200c increase contributes to brain cell death by suppressing reelin.
- Reducing miR-200c levels presents a potential therapeutic strategy for mitigating stroke-induced brain injury.
