New frontiers in RNA transport and local translation in neurons

Driesche, Sarah J. Van; Martin, Kelsey C.

doi:10.1002/dneu.22574

Cited by 47 publications

(32 citation statements)

References 53 publications

(64 reference statements)

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“…Finally the local translation of these long synaptic proteins encoding cell adhesion molecules, scaffolding proteins, channels and receptors may be responsible for changes in synaptic strength following synaptic activity as the synapses grow on both the pre-and post-synaptic sides during development and due to experience. Once localized to the synapse these mRNAs are likely maintained in a translationally repressed state during the stage of elongation until suitable synaptic signals release this repression [241][242][243][244][245][246][247][248] . This has been suggested to be a common mechanism regulating protein synthesis in neuronal processes 35,[249][250][251] .…”

Section: A Seventh Common Upstream Regulatory Pathway Dmd (Dystrophimentioning

confidence: 99%

FMRP binding to a ranked subset of long genes is revealed by coupled CLIP and TRAP in specific neuronal cell types

Driesche

Sawicka

Zhang

et al. 2019

Preprint

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Highlights 1. We have created a mouse model in which endogenous FMRP can be conditionally tagged.2. Using tag-specific CLIP we describe ranked and specific sets of in vivo FMRP mRNA targets in two types of neurons.3. This ranking was used to reveal that FMRP regulates mRNAs with long coding sequences.4. FMRP mRNA targets in Purkinje cells, including the top-ranked IP3 receptor, are related to cell-autonomous Fragile X phenotypes. 5.We have updated our previous list of whole mouse brain FMRP mRNA targets with more replicates, deeper sequencing and improved analysis 6. The use of tagged FMRP in less abundant cell populations allowed identification of novel mRNA targets missed in a whole brain analysis

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Section: A Seventh Common Upstream Regulatory Pathway Dmd (Dystrophimentioning

confidence: 99%

FMRP binding to a ranked subset of long genes is revealed by coupled CLIP and TRAP in specific neuronal cell types

Driesche

Sawicka

Zhang

et al. 2019

Preprint

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“…It has been proposed that a substantial fraction of proteome supply and remodeling occurs locally within synapses (5)(6)(7)(8). While a wealth of data has led to consensus that protein synthesis occurs in mature dendrites (7,9) there has been much less agreement about local translation in mature axons.…”

Section: Introductionmentioning

confidence: 99%

Local protein synthesis is a ubiquitous feature of neuronal pre- and postsynaptic compartments

Hafner

Donlin-Asp

Leitch

et al. 2018

Preprint

116

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Local protein synthesis is a ubiquitous feature of neuronal pre-and postsynaptic compartments.One sentence summary: Protein synthesis occurs in all synaptic compartments, including excitatory and inhibitory axon terminals. Presynaptic terminals from mouse cortex and hippocampus contain translation machineryEfforts to localize molecules or cell biological events to neuronal pre-or postsynaptic compartments using fluorescence microscopy are limited by the tight association of the axonal bouton and the dendritic spine or synapse; the synaptic cleft, the only clear region of separation, is only ~ 20 nm wide. Here, in order to increase the resolving power to visualize mRNA molecules in pre-and postsynaptic compartments, we optimized fluorescence in situ hybridization (FISH) and nascent protein detection methods for use with expansion microscopy (22) ( Fig. 1A; see Methods). We used adult mouse brain slices or rat cultured hippocampal neurons and found that expansion resulted in an enlargement of both pre-and postsynaptic compartments, with an average expansion of ~3.4 fold. This yielded a clear separation between the pre-and postsynaptic compartments. To evaluate whether ribosomes and mRNA species are present in defined presynaptic compartments, we used immunolabelling for either excitatory (vGLUT1; (23, 24) or inhibitory (vGAT; (25, 26)) nerve terminals in expanded mouse brain sections (both cortex and hippocampus) ( Fig. 1B-E) or rat cultured hippocampal neurons. We took care to identify the molecules-of-interest within individual z-sections positively labeled for excitatory or inhibitory terminals. We noted that signal detected outside of immunolabeled compartments corresponded to signal arising from nearby unlabeled cells. We detected ribosomes in a large majority (>75%) of both excitatory and inhibitory presynaptic nerve terminals, using antibodies directed against either a small (RPS11) or a large (RPL26) ribosomal protein ( Fig. 1 B-E). Next, we used FISH probes to detect 18s and 28s rRNA as well as polyadenylated mRNA (detected with a poly d(T) probe) in expanded samples ( Fig. 1B-E). Consistent with the abundance of ribosomal proteins, we detected rRNA in over 80% of both excitatory and inhibitory nerve terminals ( Fig. 1B-E). RNase treatment effectively reduced all rRNA signal. In cultured neurons, we also noted that poly(A) mRNA was abundant, as expected, in dendritic spines. In addition, we used an anti-tau antibody to label axons and detected both 18s and 28s rRNA in axonal segments. Thus, mRNAs and ribosomes were abundant in excitatory and inhibitory presynaptic nerve terminals from both mouse brain slices and rat hippocampal cultured neurons.

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“…Translational control, particularly on-site in growth cones and synapses, is central for axonal pathfinding and synaptic plasticity (Jung et al, 2014;Glock et al, 2017;Van Driesche and Martin, 2018). Thus, genetic mutations resulting in aberrant translation have been identified in neurodevelopmental diseases (Scheper et al, 2007;Wang et al, 2016), such as autism spectrum disorder (ASD), intellectual disability, and infantile epilepsy.…”

Section: Translational Control In Autism Spectrum Disordersmentioning

confidence: 99%

Dysregulated Translation in Neurodevelopmental Disorders: An Overview of Autism‐Risk Genes Involved in Translation

Chen

Chang

Huang

2018

Developmental Neurobiology

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Regulated local translation—whereby specific mRNAs are transported and localized in subcellular domains where they are translated in response to regional signals—allows for remote control of gene expression to concentrate proteins in subcellular compartments. Neurons are highly polarized cells with unique features favoring local control for axonal pathfinding and synaptic plasticity, which are key processes involved in constructing functional circuits in the developing brain. Neurodevelopmental disorders are caused by genetic or environmental factors that disturb the nervous system’s development during prenatal and early childhood periods. The growing list of genetic mutations that affect mRNA translation raises the question of whether aberrant translatomes in individuals with neurodevelopmental disorders share common molecular features underlying their stereotypical phenotypes and, vice versa, cause a certain degree of phenotypic heterogeneity. Here, we briefly give an overview of the role of local translation during neuronal development. We take the autism‐risk gene list and discuss the molecules that (perhaps) are involved in mRNA transport and translation. Both exaggerated and suppressed translation caused by mutations in those genes have been identified or suggested. Finally, we discuss some proof‐of‐principle regimens for use in autism mouse models to correct dysregulated translation.

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New frontiers in RNA transport and local translation in neurons

Cited by 47 publications

References 53 publications

FMRP binding to a ranked subset of long genes is revealed by coupled CLIP and TRAP in specific neuronal cell types

FMRP binding to a ranked subset of long genes is revealed by coupled CLIP and TRAP in specific neuronal cell types

Local protein synthesis is a ubiquitous feature of neuronal pre- and postsynaptic compartments

Dysregulated Translation in Neurodevelopmental Disorders: An Overview of Autism‐Risk Genes Involved in Translation

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