Axonal ER tubules control local translation via P180/RRBP1-mediated ribosome interactions
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1090922 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28424642_1.fastq.gz | Fastqsanger.gz | |||
| SRR28424642_2.fastq.gz | Fastqsanger.gz | |||
| SRR28424643_1.fastq.gz | Fastqsanger.gz | |||
| SRR28424643_2.fastq.gz | Fastqsanger.gz |
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Project description:Local mRNA translation in axons is critical for the spatial and temporal regulation of the axonal proteome. A wide variety of mRNAs are localized and translated in axons, however how protein synthesis is regulated at specific subcellular sites in axons remains unclear. Here, we establish that the axonal endoplasmic reticulum (ER) supports axonal translation in developing neurons. Axonal ER tubule disruption impairs local translation and ribosome distribution. Using nanoscale resolution imaging, we find that ribosomes make frequent contacts with axonal ER tubules in a translation-dependent manner and are influenced by specific extrinsic cues. We identify P180/RRBP1 as an axonally distributed ribosome receptor that regulates local translation and binds to mRNAs enriched for axonal membrane proteins. Importantly, the impairment of axonal ER – ribosome interactions causes defects in axon morphology. Our results establish an important role for the axonal ER in dynamically localizing mRNA translation which is important for proper neuron development.
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Project description:Ribosome assembly occurs mainly in the nucleolus yet recent studies have revealed robust enrichment and translation of mRNAs encoding many ribosomal proteins (RPs) in axons, far away from neuronal cell bodies. Here, we report a physical and functional interaction between locally synthesized RPs and ribosomes in the axon. We show that axonal RP translation is regulated through a novel sequence motif, CUIC, that forms an RNA-loop structure in the region immediately upstream of the initiation codon. Using imaging and subcellular proteomics techniques, we show that RPs synthesized in axons join axonal ribosomes in a nucleolus-independent fashion. Inhibition of axonal CUIC-regulated RP translation causes a significant decline in local translation activity and markedly reduces axon branching in the brain, revealing the physiological relevance of axonal RP synthesis in vivo. These results suggest that axonal translation supplies cytoplasmic RPs to maintain/modify local ribosomal function far from the nucleolus in neurons.
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Project description:Ribosome assembly occurs mainly in the nucleolus yet recent studies have revealed robust enrichment and translation of mRNAs encoding many ribosomal proteins (RPs) in axons, far away from neuronal cell bodies. Here, we report a physical and functional interaction between locally synthesized RPs and ribosomes in the axon. We show that axonal RP translation is regulated through a novel sequence motif, CUIC, that forms an RNA-loop structure in the region immediately upstream of the initiation codon. Using imaging and subcellular proteomics techniques, we show that RPs synthesized in axons join axonal ribosomes in a nucleolus-independent fashion. Inhibition of axonal CUIC-regulated RP translation causes a significant decline in local translation activity and markedly reduces axon branching in the brain, revealing the physiological relevance of axonal RP synthesis in vivo. These results suggest that axonal translation supplies cytoplasmic RPs to maintain/modify local ribosomal function far from the nucleolus in neurons.
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Project description:Local mRNA translation in axons is critical for the spatiotemporal regulation of the axonal proteome. A wide variety of mRNAs are localized and translated in axons; however, how protein synthesis is regulated at specific subcellular sites in axons remains unclear. Here, we establish that the axonal endoplasmic reticulum (ER) supports axonal translation in developing rat hippocampal cultured neurons. Axonal ER tubule disruption impairs local translation and ribosome distribution. Using nanoscale resolution imaging, we find that ribosomes make frequent contacts with axonal ER tubules in a translation-dependent manner and are influenced by specific extrinsic cues. We identify P180/RRBP1 as an axonally distributed ribosome receptor that regulates local translation and binds to mRNAs enriched for axonal membrane proteins. Importantly, the impairment of axonal ER-ribosome interactions causes defects in axon morphology. Our results establish a role for the axonal ER in dynamically localizing mRNA translation, which is important for proper neuron development.
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Project description:The identification of axonal mRNAs in model organisms has led to the discovery of many axonally translated proteins required for axon guidance and injury response. The extent to which these axonal mRNAs are conserved in humans is unknown. Here we report on the axonal transcriptome of glutamatergic neurons derived from human embryonic stem cells (hESC-neurons) grown in axon isolating microfluidic chambers. We identified mRNAs enriched in axons, representing a functionally unique local transcriptome as compared to the whole neuron transcriptome. Further, we found that the enriched functional categories within high confidence axonal transcripts resemble those in the axonal transcriptome of rat cortical neurons. Comparing our list of human axonal transcripts to similar datasets generated from embryonic and adult rat dorsal root ganglia and rat cortical neurons we found 60 mRNAs common to all four neuron types. We found that over half of these genes are associated with neurological phenotypes or diseases in model organisms and human. This data provides an important resource for studying local mRNA translation in human axons and has the potential to reveal both conserved and unique axonal mechanisms across species and neuronal types. We analyzed the axonal and whole hESC-neuron transcriptome in triplicate using the Affymetrix Human Gene 2.0 ST Array platform.
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Project description:In eukaryotic cells, the spatial regulation of protein expression is frequently conferred through the coupling of mRNA localization and the local control of translation. mRNA localization to the endoplasmic reticulum (ER) is a prominent example of such regulation and serves a ubiquitous role in segregating the synthesis of secretory and integral membrane proteins to the ER. Recent genomic and biochemical studies have now expanded this view to suggest a role for the ER in global protein synthesis. We have utilized cell fractionation and ribosome profiling to obtain a genomic survey of the subcellular organization of mRNA translation and report that ribosomal loading of mRNAs, a proxy for mRNA translation, is biased to the ER. Notably, ER-associated mRNAs encoding both cytosolic and topogenic signal-encoding proteins display similar ribosome loading densities, suggesting that ER-associated ribosomes serve a global role in mRNA translation. We propose that the partitioning of mRNAs and their translation between the cytosol and ER compartments may represent a novel mechanism for the post-transcriptional regulation of gene expression. HEK293 cells were fractionated between the cytosol and endoplasmic reticulum. Within each fraction, ribosome footprints were generated and sequenced. In parallel, total mRNA was sequenced.
2011-12-20 | E-GEOD-31539 | biostudies-arrayexpress
Project description:The identification of axonal mRNAs in model organisms has led to the discovery of many axonally translated proteins required for axon guidance and injury response. The extent to which these axonal mRNAs are conserved in humans is unknown. Here we report on the axonal transcriptome of glutamatergic neurons derived from human embryonic stem cells (hESC-neurons) grown in axon isolating microfluidic chambers. We identified mRNAs enriched in axons, representing a functionally unique local transcriptome as compared to the whole neuron transcriptome. Further, we found that the enriched functional categories within high confidence axonal transcripts resemble those in the axonal transcriptome of rat cortical neurons. Comparing our list of human axonal transcripts to similar datasets generated from embryonic and adult rat dorsal root ganglia and rat cortical neurons we found 60 mRNAs common to all four neuron types. We found that over half of these genes are associated with neurological phenotypes or diseases in model organisms and human. This data provides an important resource for studying local mRNA translation in human axons and has the potential to reveal both conserved and unique axonal mechanisms across species and neuronal types.
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