Targeting of the Arpc3 actin nucleation factor by miR-29a/b regulates dendritic spine morphology

Lippi, Giordano; Steinert, Joern R.; Marczylo, Emma L.; D’Oro, Sabina; Fiore, R.; Forsythe, Ian D.; Schratt, Gerhard; Zoli, Michèle; Nicotera, Pierluigi; Young, Kenneth W.

doi:10.1083/jcb.201103006

Cited by 131 publications

(94 citation statements)

References 66 publications

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“…The miR-29a/b cluster has also been shown to affect synapse formation and plasticity by directly targeting ARPC3, a protein which has a role in actin cytoskeleton remodeling (Lippi et al 2011). Apart from having roles in neuronal cell differentiation, miR-29a also is seen to be down-regulated in Schwann cells which are in proliferative and differentiating stages, in vitro in culture and in vivo during development, and after sciatic nerve injury (Verrier et al 2009).…”

Section: Introductionmentioning

confidence: 97%

Brain-specific knockdown of miR-29 results in neuronal cell death and ataxia in mice

Roshan

Shridhar

Sarangdhar

et al. 2014

RNA

126

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Several microRNAs have been implicated in neurogenesis, neuronal differentiation, neurodevelopment, and memory. Development of miRNA-based therapeutics, however, needs tools for effective miRNA modulation, tissue-specific delivery, and in vivo evidence of functional effects following the knockdown of miRNA. Expression of miR-29a is reduced in patients and animal models of several neurodegenerative disorders, including Alzheimer's disease, Huntington's disease, and spinocerebellar ataxias. The temporal expression pattern of miR-29b during development also correlates with its protective role in neuronal survival. Here, we report the cellular and behavioral effect of in vivo, brain-specific knockdown of miR-29. We delivered specific anti-miRNAs to the mouse brain using a neurotropic peptide, thus overcoming the blood-brain-barrier and restricting the effect of knockdown to the neuronal cells. Large regions of the hippocampus and cerebellum showed massive cell death, reiterating the role of miR-29 in neuronal survival. The mice showed characteristic features of ataxia, including reduced step length. However, the apoptotic targets of miR-29, such as Puma, Bim, Bak, or Bace1, failed to show expected levels of up-regulation in mice, following knockdown of miR-29. In contrast, another miR-29 target, voltagedependent anion channel1 (VDAC1), was found to be induced several fold in the hippocampus, cerebellum, and cortex of mice following miRNA knockdown. Partial restoration of apoptosis was achieved by down-regulation of VDAC1 in miR-29 knockdown cells. Our study suggests that regulation of VDAC1 expression by miR-29 is an important determinant of neuronal cell survival in the brain. Loss of miR-29 results in dysregulation of VDAC1, neuronal cell death, and an ataxic phenotype.

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Section: Introductionmentioning

confidence: 97%

Brain-specific knockdown of miR-29 results in neuronal cell death and ataxia in mice

Roshan

Shridhar

Sarangdhar

et al. 2014

RNA

126

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“…A number of miRNAs have been shown to be involved in specific forms of learning and memory, and dysfunction of miRNA systems is implicated in neurological and neuropsychiatric diseases including Alzheimer's, Huntington's, schizophrenia and drug addiction (Wang et al , 2012; Kocerha et al , 2015). Furthermore, a large proportion of neuronal miRNAs are enriched in dendrites, and several have been assigned roles in modulating the local translation of specific proteins involved in excitatory synaptic transmission or in regulating the actin cytoskeleton to control the morphology of dendritic spines, which house excitatory synapses (Lippi et al , 2011; Bicker et al , 2014; Hu et al , 2014, 2015; Gu et al , 2015). …”

Section: Introductionmentioning

confidence: 99%

NMDAR ‐dependent Argonaute 2 phosphorylation regulates mi RNA activity and dendritic spine plasticity

et al. 2018

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MicroRNAs (miRNAs) repress translation of target mRNAs by associating with Argonaute (Ago) proteins to form the RNA‐induced silencing complex (RISC), underpinning a powerful mechanism for fine‐tuning protein expression. Specific miRNAs are required for NMDA receptor (NMDAR)‐dependent synaptic plasticity by modulating the translation of proteins involved in dendritic spine morphogenesis or synaptic transmission. However, it is unknown how NMDAR stimulation stimulates RISC activity to rapidly repress translation of synaptic proteins. We show that NMDAR stimulation transiently increases Akt‐dependent phosphorylation of Ago2 at S387, which causes an increase in binding to GW182 and a rapid increase in translational repression of LIMK1 via miR‐134. Furthermore, NMDAR‐dependent down‐regulation of endogenous LIMK1 translation in dendrites and dendritic spine shrinkage requires phospho‐regulation of Ago2 at S387. AMPAR trafficking and hippocampal LTD do not involve S387 phosphorylation, defining this mechanism as a specific pathway for structural plasticity. This work defines a novel mechanism for the rapid transduction of NMDAR stimulation into miRNA‐mediated translational repression to control dendritic spine morphology.

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“…miRNAs have been implicated in mediating the effects of cocaine (8,9,18,22), nicotine (19,20), alcohol (41,44), and several other classes of drugs of abuse (17,33,67). In the case of cocaine addiction in rats, the upregulation of miR-181a and the downregulation of two other miRNAs, let-7d and miR124a, has been revealed in addiction-relevant regions of the brain (8).…”

mentioning

confidence: 99%

Dopamine-Regulated MicroRNA MiR-181a Controls GluA2 Surface Expression in Hippocampal Neurons

Saba

Störchel

Aksoy‐Aksel

et al. 2012

Molecular and Cellular Biology

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199

172

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The dynamic expression of AMPA-type glutamate receptors (AMPA-R) at synapses is a key determinant of synaptic plasticity, including neuroadaptations to drugs of abuse. Recently, microRNAs (miRNAs) have emerged as important posttranscriptional regulators of synaptic plasticity, but whether they target glutamate receptors to mediate this effect is not known. Here we used microarray screening to identify miRNAs that regulate synaptic plasticity within the nucleus accumbens, a brain region critical to forming drug-seeking habits. One of the miRNAs that showed a robust enrichment at medium spiny neuron synapses was miR-181a. Using bioinformatics tools, we detected a highly conserved miR-181a binding site within the mRNA encoding the GluA2 subunit of AMPA-Rs. Overexpression and knockdown of miR-181a in primary neurons demonstrated that this miRNA is a negative posttranscriptional regulator of GluA2 expression. Additionally, miR-181a overexpression reduced GluA2 surface expression, spine formation, and miniature excitatory postsynaptic current (mEPSC) frequency in hippocampal neurons, suggesting that miR-181a could regulate synaptic function. Moreover, miR-181a expression was induced by dopamine signaling in primary neurons, as well as by cocaine and amphetamines, in a mouse model of chronic drug treatment. Taken together, our results identify miR-181a as a key regulator of mammalian AMPA-type glutamate receptors, with potential implications for the regulation of drug-induced synaptic plasticity.

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Targeting of the Arpc3 actin nucleation factor by miR-29a/b regulates dendritic spine morphology

Abstract: Regulation of Arpc3 by miRNA alters dendritic spine morphology.

Cited by 131 publications

References 66 publications

Brain-specific knockdown of miR-29 results in neuronal cell death and ataxia in mice

Brain-specific knockdown of miR-29 results in neuronal cell death and ataxia in mice

NMDAR ‐dependent Argonaute 2 phosphorylation regulates mi RNA activity and dendritic spine plasticity

Dopamine-Regulated MicroRNA MiR-181a Controls GluA2 Surface Expression in Hippocampal Neurons

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