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The dynamic translatome of retinal ganglion cell axons during assembly and maintenance of the mouse visual system

ABSTRACT: Local mRNA translation mediates the adaptive responses of axons to extrinsic signals but direct evidence that it occurs in mammalian CNS axons in vivo is scant. We developed an axon-TRAP-RiboTag approach in mouse that allows deep-sequencing analysis of ribosome-bound mRNAs in the retinal ganglion cell axons of the developing and adult retinotectal projection in vivo. The embryonic-to-postnatal axonal translatome comprises an evolving subset of enriched genes with axon-specific roles suggesting distinct steps in axon wiring, such as elongation, pruning and synaptogenesis. Adult axons, remarkably, have a complex translatome with strong links to axon survival, neurotransmission and neurodegenerative disease. Translationally co-regulated mRNA subsets share common upstream regulators, and novel sequence elements generated by alternative splicing that promote axonal mRNA translation. Our results indicate that intricate regulation of compartment-specific mRNA translation in mammalian CNS axons supports the formation and maintenance of neural circuits in vivo. The profiling of ribosome-bound mRNAs in mouse retinal ganglion cell axons at 4 different developmental stages

ORGANISM(S): Mus musculus

SUBMITTER: Christine Holt

PROVIDER: E-GEOD-79352 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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The dynamic translatome of retinal ganglion cell axons during assembly and maintenance of the mouse visual system

Project description:Local mRNA translation mediates the adaptive responses of axons to extrinsic signals but direct evidence that it occurs in mammalian CNS axons in vivo is scant. We developed an axon-TRAP-RiboTag approach in mouse that allows deep-sequencing analysis of ribosome-bound mRNAs in the retinal ganglion cell axons of the developing and adult retinotectal projection in vivo. The embryonic-to-postnatal axonal translatome comprises an evolving subset of enriched genes with axon-specific roles suggesting distinct steps in axon wiring, such as elongation, pruning and synaptogenesis. Adult axons, remarkably, have a complex translatome with strong links to axon survival, neurotransmission and neurodegenerative disease. Translationally co-regulated mRNA subsets share common upstream regulators, and novel sequence elements generated by alternative splicing that promote axonal mRNA translation. Our results indicate that intricate regulation of compartment-specific mRNA translation in mammalian CNS axons supports the formation and maintenance of neural circuits in vivo.

2016-06-16 | GSE79352 | GEO

mRNA transport, translation, and decay in adult mammalian central nervous system axons

Project description:Localized mRNA translation regulates synapse function and axon maintenance, but how compartment-specific mRNA repertoires are regulated is largely unknown. We developed an axonal transcriptome capture method that allows deep sequencing of metabolically-labeled mRNAs from retinal ganglion cell axon terminals in mouse. Comparing axonal-to-somal transcriptomes and axonal translatome-to-transcriptome enables genome-wide visualization of mRNA transport and translation and unveils potential regulators tuned to each process. FMRP and TDP-43 stand out as key regulators of transport, and experiments in Fmr1 knock-out mice validate FMRP’s role in the axonal transportation of synapse-related mRNAs. Pulse-and-chase experiments enable genome-wide assessment of mRNA stability in axons and reveal a strong coupling between mRNA translation and decay. Measuring the absolute mRNA abundance per axon terminal shows that the axonal transcriptome is stably maintained in adulthood by persistent transport. Our datasets provide a rich resource for unique insights into RNA-based mechanisms in maintaining presynaptic structure and function in vivo.

2022-12-06 | GSE220187 | GEO

miR-182 regulates Slit2-mediated axon guidance by modulating the local translation of a specific mRNA

Project description:During brain wiring, mRNAs are trafficked into axons and growth cones where they are differentially translated in response to extrinsic signals. Differential control of local protein synthesis mediates neuronal compartment-specific behaviors that aid axon guidance. Yet little is understood about how specific mRNAs are selected for translation. Here we have investigated the local role of microRNAs (miRNAs) in mRNA-specific translation during axon pathfinding of Xenopus laevis retinal ganglion cell (RGC) axons. Profiling experiments revealed a rich repertoire of axonal miRNAs in developing RGC axons and identified miR-182 as one of the most abundant. Loss of miR182 impairs Slit2-induced growth cone repulsion and causes RGC axon targeting defects in vivo. To aid miRNA target prediction, we also profiled mRNA expression in RGC axons. Our results show that miR-182 targets cofilin1 mRNA in RGC growth cones and modulates its local translation in response to Slit2.

2017-01-23 | GSE86883 | GEO

Subcellular expression profiling of the growth cones of retinal ganglion cells (RGC)

Project description:Cue-directed axon guidance depends partly on local translation in growth cones. Many mRNA transcripts are known to reside in developing axons yet little is known about their subcellular distribution or, specifically, which transcripts are in growth cones. Laser capture microdissection (LCM) was used to isolate the growth cones of retinal ganglion cell (RGC) axons of two vertebrate species, mouse and Xenopus, coupled with unbiased genome-wide microarray profiling. Localized mRNA from the isolated growth cones of Xenopus laevis and Mus musculus retinal ganglion cells were subjected to microarray analysis

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Axonal ER tubules control local translation via P180/RRBP1-mediated ribosome interactions

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.

2024-04-29 | GSE262262 | GEO

Subcellular expression profiling of the growth cones of retinal ganglion cells (RGC)

2010-11-23 | GSE25166 | GEO

Multiomic Analysis of Neurons with Divergent Projection Patterns Identifies Novel Regulators of Axon Pathfinding

Project description:Axon pathfinding is a key step during the formation of neural circuits but however the transcriptional mechanisms regulating its progression remain poorly understood. The binary decision of crossing or avoiding the midline that neurons make during developmente midline that mammalian retinal ganglion cell (RGC) axons take at the optic chiasm has classically represented a robust model to search for novel mechanisms controlling the selection of axonal trajectories. Here, in order to identify new axon pathfinding regulators, we compared the transcriptome and chromatin accessibility profiles of mammalian retinal ganglion cells RGCs projecting ipsilateral (iRGCs) or contralaterally (cRGCs). Overall, our analyses retrieved dozens of new molecules potentially involved in axon pathfinding and uncovered the regulatory logic behind axon trajectories selection.

2022-08-22 | GSE184275 | GEO

Proteomic characteristics in degenerated and regenerative mouse retina

Project description:The retina constitutes a segment of the central nervous system (CNS). Both retinal and CNS neurons lack the inherent capacity to spontaneously regenerate axons following injury. Retinal ganglion cells (RGCs) serve as the neurons connecting the eyes to the brain. Diseases such as glaucoma initiate damage to RGC axons at the optic nerve, ultimately leading to cell death and irreversible vision loss. While enhancing the survival of RGCs is a crucial initial step, especially for those with pre-existing axonal injuries in the optic nerve due to prolonged insults, effective therapies should also promote axon regeneration. Neuro-regeneration and reintegration into the brain remain to be enormous challenges in neurology and ophthalmology. Despite decades of effort and resources invested in the research of neuro-regeneration, scientists are still rather far from comprehensively identifying all intrinsic axonal growth regulators and their collaborative roles. Data-independent acquisition mass spectrometry (DIA-MS) is a next-generation proteomic methodology that generates permanent digital proteome maps offering highly reproducible retrospective analysis of cellular and tissue specimens. Compared to conventional mass-spectrometry, DIA-MS provides better reproducibility and sensitivity. In this study, we employed DIA-MS to conduct a comprehensive protein expression mapping in retinas from mouse models of degeneration and regeneration, and to gain insights into the complex molecular mechanisms associated with degeneration and regeneration processes in the retina.

2024-07-29 | PXD049992 | Pride

Regulated local synthesis of ribosomal proteins maintains ribosome function in axons

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.

2019-12-11 | GSE135502 | GEO

Augmenting fibronectin levels in injured adult CNS promotes axon regeneration in vivo [bulk RNA-seq]

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