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A brain-specific microRNA regulates dendritic spine development

A Corrigendum to this article was published on 15 June 2006


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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Figure 1: miR-134 is specifically expressed in the brain and localized to neuronal dendrites.
Figure 2: miR-134 negatively regulates dendritic spine size in hippocampal neurons.
Figure 3: Limk1 mRNA is a putative miR-134 target.
Figure 4: miR-134 inhibits Limk1 mRNA translation in neurons.
Figure 5: Limk1 expression rescues miR-134-mediated reduction in spine size.
Figure 6: miR-134 is involved in BDNF-induced Limk1 mRNA translation.

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We thank D. Bartel for providing the lin-41 reporter constructs and northern blot protocols, K. Mizuno for the rat Limk1 cDNA, G. Corfas for initial help with ISH, Y. Lin and A. West for reagents, J. Bikoff, E. Griffith, E. Hong, S. Paradis and B. Sabatini for critically reading the manuscript, and all the members of the Greenberg laboratory for support and discussion. This work was supported by grants from the NINDS and NICHD (M.E.G.), HFSP (G.S. and M.K.), the Charles Hood Foundation (G.S.), the Hertie-Foundation (M.K.), the Schram-Stiftung (M.K.) and a Boehringer Ingelheim Fonds fellowship (F.T.). M.E.G. acknowledges the generous support of the F. M. Kirby Foundation to the Neurobiology Program of Children's Hospital.

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Correspondence to Michael E. Greenberg.

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Supplementary information

Supplementary Figure 1

This figure shows an RPA analysis of miR-134 expression in adult tissues, quantification of in situ hybridization analysis of miR-134 in hippocampal neurons and an RT–PCR analysis demonstrating activity-dependent regulation of miR-134 precursor expression. (PDF 1172 kb)

Supplementary Figure 2

This figure illustrates the generation of stem-loop precursor and mature miR-134 from the pcDNA3 expression vector in 293T cells. In addition, results from a microRNA sensor assay in cortical neurons are shown demonstrating efficient expression of exogenous miR-134 and inhibition of miR-134 by the 2′ OMe antisense oligonucleotide. (PDF 903 kb)

Supplementary Figure 3

This figure shows the analysis of dendritic complexity and spine number in neurons with perturbed miR-134 function, as well as the effects of synthetic double-stranded miR-134 on dendritic spine size when transfected into hippocampal neurons at various developmental stages. (PDF 887 kb)

Supplementary Figure 4

This figure shows an in vitro interaction between miR-134 and the Limk1 3′ UTR using an electrophoretic mobility shift assay. (PDF 366 kb)

Supplementary Figure 5

This figure shows localization of endogenous Limk1 mRNA in hippocampal neurons as assessed by in situ hybridization, enrichment of Limk1 mRNA in synaptoneurosomes and dendritic localization of chimeric GFP–Limk1-3′ UTR RNAs. (PDF 785 kb)

Supplementary Figure 6

This figure summarizes luciferase assays with Limk1 3′ UTR reporter genes together with microRNAs and antisense 2′OMe oligonucleotides in 293Tcells. Furthermore, a real-time RT–PCR analysis is provided demonstrating unaltered luciferase mRNA levels in cortical neurons upon transfection of synthetic microRNAs. (PDF 748 kb)

Supplementary Methods

A file describing additional methods not mentioned in the main body of the text and oligonucleotide sequences. (DOC 30 kb)

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Schratt, G., Tuebing, F., Nigh, E. et al. A brain-specific microRNA regulates dendritic spine development. Nature 439, 283–289 (2006).

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