Schratt, G, Tuebing, F, Nigh, EA, Kane, CG, Sabatini, ME, Kiebler, M et al.. A brain-specific microRNA regulates dendritic spine development. Nature 439: 283-289

Neurobiology Program, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature (Impact Factor: 41.46). 02/2006; 439(7074):283-9. DOI: 10.1038/nature04367
Source: PubMed


MicroRNAs are small, non-coding RNAs that control the translation of target messenger RNAs, thereby regulating critical aspects of plant and animal development. In the mammalian nervous system, the spatiotemporal control of mRNA translation has an important role in synaptic development and plasticity. Although a number of microRNAs have been isolated from the mammalian brain, neither the specific microRNAs that regulate synapse function nor their target mRNAs have been identified. Here we show that a brain-specific microRNA, miR-134, is localized to the synapto-dendritic compartment of rat hippocampal neurons and negatively regulates the size of dendritic spines--postsynaptic sites of excitatory synaptic transmission. This effect is mediated by miR-134 inhibition of the translation of an mRNA encoding a protein kinase, Limk1, that controls spine development. Exposure of neurons to extracellular stimuli such as brain-derived neurotrophic factor relieves miR-134 inhibition of Limk1 translation and in this way may contribute to synaptic development, maturation and/or plasticity.

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Available from: Michael A Kiebler, Jan 06, 2014
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    • "play important roles in multiple biological processes, including brain development (Krichevsky et al., 2003), synapse formation (Schratt et al., 2006), synaptic plasticity (Smalheiser and Lugli, 2009; Cohen et al., 2011), and neuroimmune signaling (Soreq and Wolf, 2011). microRNAs control both translational repression and degradation , and they also act in concert with RNA-binding proteins to pinpoint their target mRNAs, which often occurs through interaction with cis-acting elements. "
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    ABSTRACT: Local translation of mRNAs is a mechanism by which cells can rapidly remodel synaptic structure and function. There is ample evidence for a role of synaptic translation in the neuroadaptations resulting from chronic drug use and abuse. Persistent and coordinated changes of many mRNAs, globally and locally, may have a causal role in complex disorders such as addiction. In this review we examine the evidence that translational regulation by microRNAs drives synaptic remodeling and mRNA expression, which may regulate the transition from recreational to compulsive drug use. microRNAs are small, non-coding RNAs that control the translation of mRNAs in the cell and within spatially restricted sites such as the synapse. microRNAs typically repress the translation of mRNAs into protein by binding to the 3'UTR of their targets. As 'master regulators' of many mRNAs, changes in microRNAs could account for the systemic alterations in mRNA and protein expression observed with drug abuse and dependence. Recent studies indicate that manipulation of microRNAs affects addiction-related behaviors such as the rewarding properties of cocaine, cocaine-seeking behavior, and self-administration rates of alcohol. There is limited evidence, however, regarding how synaptic microRNAs control local mRNA translation during chronic drug exposure and how this contributes to the development of dependence. Here, we discuss research supporting microRNA regulation of local mRNA translation and how drugs of abuse may target this process. The ability of synaptic microRNAs to rapidly regulate mRNAs provides a discrete, localized system that could potentially be used as diagnostic and treatment tools for alcohol and other addiction disorders.
    Full-text · Article · Dec 2014 · Frontiers in Molecular Neuroscience
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    • "microRNAs (miRNAs) comprise a specific class of small noncoding RNAs that bind to complementary sequences on target mRNAs to repress translation and silence gene expression (Ambros, 2001; Lee & Ambros, 2001) and are key regulators of cellular gene expression. They are highly abundant in brain and mediate multiple biological processes, including brain development (Krichevsky, King, Donahue, Khrapko, & Kosik, 2003), synapse formation (Schratt et al., 2006), synaptic plasticity (Cohen, Lee, Chen, Li, & Fields, 2011; Smalheiser & Lugli, 2009), and neuroimmune signaling (Soreq & Wolf, 2011). miRNAs are capable of eliciting targeted actions in innate immunity-and epigenetic-related functions in glial cells (Nunez & Mayfield, 2012) and have been associated with development of the immune system and regulation of multiple immune functions (O'Neill, Sheedy, & McCoy, 2011). "
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    ABSTRACT: Immune or brain proinflammatory signaling has been linked to some of the behavioral effects of alcohol. Immune signaling appears to regulate voluntary ethanol intake in rodent models, and ethanol intake activates the immune system in multiple models. This bidirectional link raises the possibility that consumption increases immune signaling, which in turn further increases consumption in a feed-forward cycle. Data from animal and human studies provide overlapping support for the involvement of immune-related genes and proteins in alcohol action, and combining animal and human data is a promising approach to systematically evaluate and nominate relevant pathways. Based on rodent models, neuroimmune pathways may represent unexplored, nontraditional targets for medication development to reduce alcohol consumption and prevent relapse. Peroxisome proliferator-activated receptor agonists are one class of anti-inflammatory medications that demonstrate antiaddictive properties for alcohol and other drugs of abuse. Expression of immune-related genes is altered in animals and humans following chronic alcohol exposure, and the regulatory influences of specific mRNAs, microRNAs, and activated cell types are areas of intense study. Ultimately, the use of multiple datasets combined with behavioral validation will be needed to link specific neuroimmune pathways to addiction vulnerability.
    Full-text · Article · Sep 2014 · International Review of Neurobiology
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    • "Interestingly HAR1F is specifically expressed in the fetal brain in Cajal–Retzius neurons along with reelin a gene critical in the specification of layering in the cortex (16915236). As might be expected, there are many single examples of changes in expression of ncRNAs as the brain develops (Barry, 2014; Iyengar et al., 2014; Nowak & Michlewski, 2013), including instances where a neuronal specific function is impacted by miRNA expression levels during development (Schratt et al., 2006). "
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    ABSTRACT: The transcriptome changes hugely during development of the brain. Whole genes, alternate exons, and single base pair changes related to RNA editing all show differences between embryonic and mature brain. Collectively, these changes control proteomic diversity as the brain develops. Additionally, there are many changes in noncoding RNAs (miRNA and lncRNA) that interact with mRNA to influence the overall transcriptional landscape. Here, we will discuss what is known about such changes in brain development, particularly focusing on high-throughput approaches and how those can be used to infer mechanisms by which gene expression is controlled in the brain as it matures.
    Full-text · Article · Aug 2014 · International Review of Neurobiology
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