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A boost in microRNAs shapes up the neuron.

Muddashetty R, Bassell GJ - EMBO J. (2009)

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, Emory University, Atlanta, GA 30322, USA.

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MicroRNAs have emerged as a powerful class of conserved noncoding RNAs that regulate gene expression post-transcriptionally and have important functions in numerous aspects of development... In this issue, show that the gene cluster miR379–410, which includes up to 50 microRNA genes, is induced by neuronal depolarization and has an important function in dendritic development in cultured neurons (Figure 1). miR-134, a member of this cluster, was earlier shown to be localized to dendrites of cultured hippocampal neurons, where it regulates dendritic spine morphology by its reversible inhibitory effect on LimK1 mRNA in response to BDNF... In a series of elegant and well-integrated experiments to inhibit miRNA function, mutate miRNA-binding sites in target reporters, and use of siRNA to knockdown Mef2 expression, the authors provide compelling evidence that Mef2 was necessary for the activation of this microRNA gene cluster... Neuronal depolarization increased a subset of microRNA expression, which appears to have a significant effect on early dendritogenesis in cultured neurons... Increased miRNAs were linked to the increased complexity of dendritic arborization of stimulated neurons... Interestingly, only a few members of this miRNA cluster had a positive impact on the dendritic arborization, while others had no effect... Knockdown of the transcription factor, Mef2, prevented the stimulus-induced increase in microRNAs (from the miR379–410 cluster) and also diminished the dendritic complexity... This finding is significant in its demonstration that a global response (transcriptional activation mediated by Mef2) is necessary for a local effect (dendritic arborization)... In an exciting addition to this story, have identified Pumilio2 as a target of miR-134 whose inhibition is essential for activity-dependent dendritogenesis... During early stages of culture (DIV5-7), KCl or BDNF stimulation was shown in this study to promote miR-134 mediated inhibition of translation (Pumilio2), which facilitates dendritogenesis; however, at later stages (DIV14), similar stimulation paradigms actually relieve miR-134 mediated translational inhibition (LimK1) leading to increased size of spines... More work is also needed to understand the mechanistic details of the possible dual nature of miR-134 function (either inducing or relieving the translation inhibition upon stimulation), and whether these activities may be bidirectionally regulated in dendrites in response to physiological patterns of neuronal activity... The physiological significance of the microRNA pathway and its regulation in neuronal development is evident by its involvement in several neurological disorders, including fragile X syndrome, which is caused by the loss of FMRP... FMRP is an mRNA-binding protein that regulates synaptic protein synthesis and also associated with microRNA pathway... The significant defects in spine morphology and dendritogenesis seen in disorders such as fragile X syndrome have not been effectively reconciled at a mechanistic level.

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MicroRNAs from the miR379–410 cluster regulate dendritogenesis. Neuronal activity induces several microRNAs from the miR379–410 cluster in an Mef2-mediated pathway. One of these, miR-134, inhibits Pumilio2 protein synthesis essential for dendritogenesis.
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f1: MicroRNAs from the miR379–410 cluster regulate dendritogenesis. Neuronal activity induces several microRNAs from the miR379–410 cluster in an Mef2-mediated pathway. One of these, miR-134, inhibits Pumilio2 protein synthesis essential for dendritogenesis.

Mentions: Many microRNA genes are arranged in clusters. In this issue, Fiore et al (2009) show that the gene cluster miR379–410, which includes up to 50 microRNA genes, is induced by neuronal depolarization and has an important function in dendritic development in cultured neurons (Figure 1). miR-134, a member of this cluster, was earlier shown to be localized to dendrites of cultured hippocampal neurons, where it regulates dendritic spine morphology by its reversible inhibitory effect on LimK1 mRNA in response to BDNF (Schratt et al, 2006). Here, Fiore et al provide evidence that these miRNAs are likely expressed from a single transcript, which is induced by neuronal activity (treatment with KCl or BDNF). The transcription factor, Mef2, was shown to bind an upstream element on this miRNA gene cluster and activate transcription upon stimulation. Mef2 was previously shown to be key negative regulator of activity-dependent synapse development (Flavell et al, 2006), whose target genes likely play diverse functions at synapses (Flavell et al, 2008). Chromatin immunoprecipitation assays identified Mef2 as the transcription factor for the miR379–410 cluster. In a series of elegant and well-integrated experiments to inhibit miRNA function, mutate miRNA-binding sites in target reporters, and use of siRNA to knockdown Mef2 expression, the authors provide compelling evidence that Mef2 was necessary for the activation of this microRNA gene cluster. Neuronal depolarization increased a subset of microRNA expression, which appears to have a significant effect on early dendritogenesis in cultured neurons. Increased miRNAs were linked to the increased complexity of dendritic arborization of stimulated neurons. Interestingly, only a few members of this miRNA cluster had a positive impact on the dendritic arborization, while others had no effect. This opens up the possibility that other microRNAs, which are also significantly induced by stimulation, might regulate other aspects of neuronal development and synapse formation. Knockdown of the transcription factor, Mef2, prevented the stimulus-induced increase in microRNAs (from the miR379–410 cluster) and also diminished the dendritic complexity. This finding is significant in its demonstration that a global response (transcriptional activation mediated by Mef2) is necessary for a local effect (dendritic arborization).


A boost in microRNAs shapes up the neuron.

Muddashetty R, Bassell GJ - EMBO J. (2009)

MicroRNAs from the miR379–410 cluster regulate dendritogenesis. Neuronal activity induces several microRNAs from the miR379–410 cluster in an Mef2-mediated pathway. One of these, miR-134, inhibits Pumilio2 protein synthesis essential for dendritogenesis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2666025&req=5

f1: MicroRNAs from the miR379–410 cluster regulate dendritogenesis. Neuronal activity induces several microRNAs from the miR379–410 cluster in an Mef2-mediated pathway. One of these, miR-134, inhibits Pumilio2 protein synthesis essential for dendritogenesis.
Mentions: Many microRNA genes are arranged in clusters. In this issue, Fiore et al (2009) show that the gene cluster miR379–410, which includes up to 50 microRNA genes, is induced by neuronal depolarization and has an important function in dendritic development in cultured neurons (Figure 1). miR-134, a member of this cluster, was earlier shown to be localized to dendrites of cultured hippocampal neurons, where it regulates dendritic spine morphology by its reversible inhibitory effect on LimK1 mRNA in response to BDNF (Schratt et al, 2006). Here, Fiore et al provide evidence that these miRNAs are likely expressed from a single transcript, which is induced by neuronal activity (treatment with KCl or BDNF). The transcription factor, Mef2, was shown to bind an upstream element on this miRNA gene cluster and activate transcription upon stimulation. Mef2 was previously shown to be key negative regulator of activity-dependent synapse development (Flavell et al, 2006), whose target genes likely play diverse functions at synapses (Flavell et al, 2008). Chromatin immunoprecipitation assays identified Mef2 as the transcription factor for the miR379–410 cluster. In a series of elegant and well-integrated experiments to inhibit miRNA function, mutate miRNA-binding sites in target reporters, and use of siRNA to knockdown Mef2 expression, the authors provide compelling evidence that Mef2 was necessary for the activation of this microRNA gene cluster. Neuronal depolarization increased a subset of microRNA expression, which appears to have a significant effect on early dendritogenesis in cultured neurons. Increased miRNAs were linked to the increased complexity of dendritic arborization of stimulated neurons. Interestingly, only a few members of this miRNA cluster had a positive impact on the dendritic arborization, while others had no effect. This opens up the possibility that other microRNAs, which are also significantly induced by stimulation, might regulate other aspects of neuronal development and synapse formation. Knockdown of the transcription factor, Mef2, prevented the stimulus-induced increase in microRNAs (from the miR379–410 cluster) and also diminished the dendritic complexity. This finding is significant in its demonstration that a global response (transcriptional activation mediated by Mef2) is necessary for a local effect (dendritic arborization).

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, Emory University, Atlanta, GA 30322, USA.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

MicroRNAs have emerged as a powerful class of conserved noncoding RNAs that regulate gene expression post-transcriptionally and have important functions in numerous aspects of development... In this issue, show that the gene cluster miR379–410, which includes up to 50 microRNA genes, is induced by neuronal depolarization and has an important function in dendritic development in cultured neurons (Figure 1). miR-134, a member of this cluster, was earlier shown to be localized to dendrites of cultured hippocampal neurons, where it regulates dendritic spine morphology by its reversible inhibitory effect on LimK1 mRNA in response to BDNF... In a series of elegant and well-integrated experiments to inhibit miRNA function, mutate miRNA-binding sites in target reporters, and use of siRNA to knockdown Mef2 expression, the authors provide compelling evidence that Mef2 was necessary for the activation of this microRNA gene cluster... Neuronal depolarization increased a subset of microRNA expression, which appears to have a significant effect on early dendritogenesis in cultured neurons... Increased miRNAs were linked to the increased complexity of dendritic arborization of stimulated neurons... Interestingly, only a few members of this miRNA cluster had a positive impact on the dendritic arborization, while others had no effect... Knockdown of the transcription factor, Mef2, prevented the stimulus-induced increase in microRNAs (from the miR379–410 cluster) and also diminished the dendritic complexity... This finding is significant in its demonstration that a global response (transcriptional activation mediated by Mef2) is necessary for a local effect (dendritic arborization)... In an exciting addition to this story, have identified Pumilio2 as a target of miR-134 whose inhibition is essential for activity-dependent dendritogenesis... During early stages of culture (DIV5-7), KCl or BDNF stimulation was shown in this study to promote miR-134 mediated inhibition of translation (Pumilio2), which facilitates dendritogenesis; however, at later stages (DIV14), similar stimulation paradigms actually relieve miR-134 mediated translational inhibition (LimK1) leading to increased size of spines... More work is also needed to understand the mechanistic details of the possible dual nature of miR-134 function (either inducing or relieving the translation inhibition upon stimulation), and whether these activities may be bidirectionally regulated in dendrites in response to physiological patterns of neuronal activity... The physiological significance of the microRNA pathway and its regulation in neuronal development is evident by its involvement in several neurological disorders, including fragile X syndrome, which is caused by the loss of FMRP... FMRP is an mRNA-binding protein that regulates synaptic protein synthesis and also associated with microRNA pathway... The significant defects in spine morphology and dendritogenesis seen in disorders such as fragile X syndrome have not been effectively reconciled at a mechanistic level.

Show MeSH