RESEARCH HIGHLIGHTS Nature Reviews Neuroscience | AOP, published online 12 February 2014; doi:10.1038/nrn3697
SYNAPTIC PLASTICITY
Unmasked: dendritic mRNA dynamics neuronal stimulation enhances the release of mRNAs from the mRNP complexes: a process that might act to ‘unmask’ the mRNA
Local translation of proteins in dendrites is thought to contribute to synaptic plasticity. According to this model, dendritic mRNAs are held in a repressed state until synaptic activity prompts their translation; however, the molecular mechanisms underlying this process are unclear. By exploiting techniques that enable the visualization of single mRNA molecules, two papers reveal the mechanisms by which ‘masked’ β-actin mRNA is retained in dendrites and subsequently ‘unmasked’ by neuronal activity. Our understanding of the movements and behaviour of locally translated mRNAs has been hampered by difficulties in visualizing endogenous mRNA molecules. In their new study, Park et al. generated transgenic mice in which all
J. Vallis/NPG
endogenous β-actin mRNA was fluorescently labelled. This approach eliminated the potential confounding effects of the introduction of exogenous material into a cell and enabled the authors to track the movements of individual β-actin mRNAs in living cells. Park et al. showed that the cell bodies and dendrites of cultured hippocampal neurons contained messenger ribonucleoprotein particles (mRNPs) — complexes of mRNAs with proteins involved in their regulation and transport — holding single or multiple copies of β-actin mRNA. Depolarization of the neurons with potassium chloride resulted in an increase in the number of mRNPs containing single β-actin mRNA molecules, suggesting that neuronal stimulation enhances the release of mRNAs from the mRNP complexes: a process that might act to ‘unmask’ the mRNA and thereby make it available for translation. In the second study, Buxbaum et al. examined this activity-induced unmasking in greater detail. The authors used single mRNA fluorescent in situ hybridization (FISH) in fixed cultured mouse hippocampal neurons to detect individual endogenous β-actin mRNAs. They observed an increase in the number of β-actin mRNAs available for probe binding — assumed to be unmasked mRNAs — in cells exposed to chemically induced long-term potentiation (cLTP), a form of synaptic plasticity. Next, Buxbaum et al. sought to confirm that masking of β-actin mRNA involves an association with mRNPs. Treatment of the cells with
NATURE REVIEWS | NEUROSCIENCE
a protease mimicked the effects of cLTP, indicating that release from a protein complex is involved in mRNA unmasking. The levels and dispersal of ribosomal RNA were also increased by cLTP, suggesting that ribosomes — which are components of the mRNP complex — are also released during the mRNA unmasking. Furthermore, knockout of either fragile X mental retardation protein (FMRP) or Z-DNA binding protein 1 (ZBP1), which are components of mRNPs, decreased the number of masked β-actin mRNAs in the absence of stimulation. What are the mechanisms that link synaptic activity to the unmasking of β-actin mRNA? Blocking either synaptic NMDA receptors or molecules downstream of NMDA signalling abolished the effects of cLTP, suggesting that these signals mediate the release of the mRNA from the mRNP. These findings indicate that β-actin mRNA is present in dendrites as part of an mRNP complex that prevents it from actively translating and that synaptic activity unmasks the RNA by stimulating complex disassembly. The extent to which similar mechanisms are exploited by other mRNAs and other cell types remains to be determined. Katherine Whalley ORIGINAL RESEARCH PAPERS Park, H. Y. et al. Visualization of dynamics of single endogenous mRNA labeled in live mouse. Science 343, 422–424 (2014) | Buxbaum, A. R., Wu, B. & Singer, R. H. Single β-actin mRNA detection in neurons reveals a mechanism for regulating its translatability. Science 343, 419–422 (2014)
VOLUME 15 | MARCH 2014 © 2014 Macmillan Publishers Limited. All rights reserved
SYNAPTIC PLASTICITY
Unmasked: dendritic mRNA dynamics neuronal stimulation enhances the release of mRNAs from the mRNP complexes: a process that might act to ‘unmask’ the mRNA
Local translation of proteins in dendrites is thought to contribute to synaptic plasticity. According to this model, dendritic mRNAs are held in a repressed state until synaptic activity prompts their translation; however, the molecular mechanisms underlying this process are unclear. By exploiting techniques that enable the visualization of single mRNA molecules, two papers reveal the mechanisms by which ‘masked’ β-actin mRNA is retained in dendrites and subsequently ‘unmasked’ by neuronal activity. Our understanding of the movements and behaviour of locally translated mRNAs has been hampered by difficulties in visualizing endogenous mRNA molecules. In their new study, Park et al. generated transgenic mice in which all
J. Vallis/NPG
endogenous β-actin mRNA was fluorescently labelled. This approach eliminated the potential confounding effects of the introduction of exogenous material into a cell and enabled the authors to track the movements of individual β-actin mRNAs in living cells. Park et al. showed that the cell bodies and dendrites of cultured hippocampal neurons contained messenger ribonucleoprotein particles (mRNPs) — complexes of mRNAs with proteins involved in their regulation and transport — holding single or multiple copies of β-actin mRNA. Depolarization of the neurons with potassium chloride resulted in an increase in the number of mRNPs containing single β-actin mRNA molecules, suggesting that neuronal stimulation enhances the release of mRNAs from the mRNP complexes: a process that might act to ‘unmask’ the mRNA and thereby make it available for translation. In the second study, Buxbaum et al. examined this activity-induced unmasking in greater detail. The authors used single mRNA fluorescent in situ hybridization (FISH) in fixed cultured mouse hippocampal neurons to detect individual endogenous β-actin mRNAs. They observed an increase in the number of β-actin mRNAs available for probe binding — assumed to be unmasked mRNAs — in cells exposed to chemically induced long-term potentiation (cLTP), a form of synaptic plasticity. Next, Buxbaum et al. sought to confirm that masking of β-actin mRNA involves an association with mRNPs. Treatment of the cells with
NATURE REVIEWS | NEUROSCIENCE
a protease mimicked the effects of cLTP, indicating that release from a protein complex is involved in mRNA unmasking. The levels and dispersal of ribosomal RNA were also increased by cLTP, suggesting that ribosomes — which are components of the mRNP complex — are also released during the mRNA unmasking. Furthermore, knockout of either fragile X mental retardation protein (FMRP) or Z-DNA binding protein 1 (ZBP1), which are components of mRNPs, decreased the number of masked β-actin mRNAs in the absence of stimulation. What are the mechanisms that link synaptic activity to the unmasking of β-actin mRNA? Blocking either synaptic NMDA receptors or molecules downstream of NMDA signalling abolished the effects of cLTP, suggesting that these signals mediate the release of the mRNA from the mRNP. These findings indicate that β-actin mRNA is present in dendrites as part of an mRNP complex that prevents it from actively translating and that synaptic activity unmasks the RNA by stimulating complex disassembly. The extent to which similar mechanisms are exploited by other mRNAs and other cell types remains to be determined. Katherine Whalley ORIGINAL RESEARCH PAPERS Park, H. Y. et al. Visualization of dynamics of single endogenous mRNA labeled in live mouse. Science 343, 422–424 (2014) | Buxbaum, A. R., Wu, B. & Singer, R. H. Single β-actin mRNA detection in neurons reveals a mechanism for regulating its translatability. Science 343, 419–422 (2014)
VOLUME 15 | MARCH 2014 © 2014 Macmillan Publishers Limited. All rights reserved
