Ischemic preconditioning regulates expression of microRNAs and a predicted target, MeCP2, in mouse cortex

Robert S. Dow Neurobiology Laboratories, Legacy Research, Portland, Oregon 97232, USA.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism (Impact Factor: 5.41). 12/2009; 30(4):744-56. DOI: 10.1038/jcbfm.2009.253
Source: PubMed


Preconditioning describes the ischemic stimulus that triggers an endogenous, neuroprotective response that protects the brain during a subsequent severe ischemic injury, a phenomenon known as 'tolerance'. Ischemic tolerance requires new protein synthesis, leads to genomic reprogramming of the brain's response to subsequent ischemia, and is transient. MicroRNAs (miRNAs) regulate posttranscriptional gene expression by exerting direct effects on messenger RNA (mRNA) translation. We examined miRNA expression in mouse cortex in response to preconditioning, ischemic injury, and tolerance. The results of our microarray analysis revealed that miRNA expression is consistently altered within each group, but that preconditioning was the foremost regulator of miRNAs. Our bioinformatic analysis results predicted that preconditioning-regulated miRNAs most prominently target mRNAs that encode transcriptional regulators; methyl-CpG binding protein 2 (MeCP2) was the most prominent target. No studies have linked MeCP2 to preconditioning or tolerance, yet miR-132, which regulates MeCP2 expression, is decreased in preconditioned cortex. Downregulation of miR-132 is consistent with our finding that preconditioning ischemia induces a rapid increase in MeCP2 protein, but not mRNA, in mouse cortex. These studies reveal that ischemic preconditioning regulates expression of miRNAs and their predicted targets in mouse brain cortex, and further suggest that miRNAs and MeCP2 could serve as effectors of ischemic preconditioning-induced tolerance.

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Available from: Giuseppe Pignataro, Feb 12, 2014
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    • "In conclusion, our work identifies a regulatory pathway involving miR-132 and the miR-132 target Ctbp2, as well as Rest and Sirt1, which explains the dynamics of Notch signaling to set the timing of early radial glial differentiation and maturation in the developing spinal cord. miR-132 downregulation has also been associated with several CNS disorders, including Alzheimer's disease (AD), multiple sclerosis (MS), and ischemic stroke, paralleling increased CTBP2 and Notch levels (Desai et al., 2009; John et al., 2002; Lau et al., 2013; Lescher et al., 2012; Lusardi et al., 2010; Nagarsheth et al., 2006; Tseveleki et al., 2010; Wang et al., 2009). These disorders are characterized by compromised neuronal regeneration, impaired myelination , and neurodegeneration; and it is interesting that activation of SIRT1 has been proposed as a therapeutic approach in AD, MS, Parkinson's disease, and stroke (Bonda et al., 2011; Donmez , 2012; Nimmagadda et al., 2013). "
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    ABSTRACT: Radial glial progenitors play pivotal roles in the development and patterning of the spinal cord, and their fate is controlled by Notch signaling. How Notch is shaped to regulate their crucial transition from expansion toward differentiation remains, however, unknown. miR-132 in the developing zebrafish dampens Notch signaling via a cascade involving the transcriptional corepressor Ctbp2 and the Notch suppressor Sirt1. At early embryonic stages, high Ctbp2 levels sustain Notch signaling and radial glial expansion and concomitantly induce miR-132 expression via a double-negative feedback loop involving Rest inhibition. The changing balance in miR-132 and Ctbp2 interaction gradually drives the switch in Notch output and radial glial progenitor fate as part of the larger developmental program involved in the transition from embryonic to larval spinal cord.
    Full-text · Article · Aug 2014 · Developmental Cell
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    • "MiRNAs have been implicated in the regulation of numerous physiological and pathological processes such as brain differentiation (Feng and Feng, 2011), neurological disorders (Saugstad, 2010), ischemic preconditioning (Lusardi et al., 2010), and stroke (Rink and Khanna, 2011; Tan et al., 2011). The few studies which have examined miRNA responses to injury in brain have either focused on irradiation injury (Ilnytskyy et al., 2008; Koturbash et al., 2011), evaluated a single miRNA target of interest following brain ischemia (Siegel et al., 2011), or profiled miRNAs in male ischemic brain without linking them functionally to ischemic mechanisms and outcomes (Jeyaseelan et al., 2008; Dharap et al., 2009; Liu et al., 2010; Lusardi et al., 2010). "
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    ABSTRACT: Stroke occurs with greater frequency in men than in women across diverse ethnic backgrounds and nationalities. Work from our lab and others have revealed a sex-specific sensitivity to cerebral ischemia whereby males exhibit a larger extent of brain damage resulting from an ischemic event compared to females. Previous studies revealed that microRNA (miRNA) expression is regulated by cerebral ischemia in males; however, no studies to date have examined the effect of ischemia on miRNA responses in females. Thus, we examined miRNA responses in male and female brain in response to cerebral ischemia using miRNA arrays. These studies revealed that in male and female brains, ischemia leads to both a universal miRNA response as well as a sexually distinct response to challenge. Target prediction analysis of the miRNAs increased in male or female ischemic brain reveal sex-specific differences in gene targets and protein pathways. These data support that the mechanisms underlying sexually dimorphic responses to cerebral ischemia includes distinct changes in miRNAs in male and female brain, in addition to a miRNA signature response to ischemia that is common to both.
    Full-text · Article · Feb 2014 · Frontiers in Molecular Neuroscience
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    • "They also found that members in miR-200 family could downregulate proline hydroxylase (PHD2) to reduce neuronal death. In another study, miR-132 family was found to bind to methyl-CpG binding protein 2, which resulted in upregulation in itself and improvement of IPC [35]. These findings suggest that IPC may regulate the miRNA expression to activate neuroprotection related signaling pathways in case of ischemia, which then reduce the ischemic injury to neurons after stroke. "
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    ABSTRACT: microRNAs (miRNA), a sort of noncoding RNAs widely distributed in eukaryotic cells, could regulate gene expression by inhibiting transcription or translation. They were involved in important physiological and pathological processes including growth, development, and occurrence and progression of diseases. miRNAs are crucial for the development of the nervous system. Recent studies have demonstrated that some miRNAs play important roles in the occurrence and development of ischemic cerebrovascular diseases such as stroke and were also involved in the occurrence and development of poststroke depression (PSD). Herein, studies on the role of miRNAs in the cerebral ischemia and PSD were reviewed, and results may be helpful for the diagnosis and prognosis of cerebral ischemia and PSD with miRNAs in clinical practice.
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