Regulation of NGF Signaling by an Axonal Untranslated mRNA

Crerar, Hamish; Scott-Solomon, Emily; Bodkin-Clarke, Chantal; Andreassi, Catia; Hazbon, Maria; Logie, Emilie; Cano-Jaimez, Marifé; Gaspari, Marco; Kuruvilla, Rejji; Riccio, Antonella

doi:10.1016/j.neuron.2019.02.011

Cited by 40 publications

(50 citation statements)

References 45 publications

(55 reference statements)

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“…However, there could be many additional reasons for RNA localization that are not yet clear. For example, the RNAs themselves might have a function as is the case for many non‐coding RNAs (eg, miRNAs and lncRNAs) and at least one mRNA 50 …”

Section: How Does Rna Get There?mentioning

confidence: 99%

Mechanisms and consequences of subcellularRNAlocalization across diverse cell types

Engel

Arora

Goering

et al. 2020

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Essentially all cells contain a variety of spatially restricted regions that are important for carrying out specialized functions. Often, these regions contain specialized transcriptomes that facilitate these functions by providing transcripts for localized translation. These transcripts play a functional role in maintaining cell physiology by enabling a quick response to changes in the cellular environment. Here, we review how RNA molecules are trafficked within cells, with a focus on the subcellular locations to which they are trafficked, mechanisms that regulate their transport and clinical disorders associated with misregulation of the process. K E Y W O R D SRNA binding protein, RNA cis-element, RNA localization, RNA transport, zipcode

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Section: How Does Rna Get There?mentioning

confidence: 99%

Mechanisms and consequences of subcellularRNAlocalization across diverse cell types

Engel

Arora

Goering

et al. 2020

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“…For example, eIF3d, an initiation factor previously shown to 406 regulate specialized translation initiation, is significantly enriched specifically in Nrp1 IP, but 407 not DCC IP, thus raising the interesting possibility that differential binding to initiation factors 408 may contribute to cue-induced selective translation (Lee et al, 2016). Intriguingly, a recent 409 study revealed that an untranslated mRNA can associate with and regulate the signalling of 410 the TrkA receptor in axons via its axon-enriched long 3'UTR (Crerar et al, 2019). It will be 411 interesting to investigate whether any of the DCC and Nrp1 targets identified in our study 412 also play a structural role, for example by regulating the receptor-ribosome association 413 and/or the downstream signalling and local translation.…”

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confidence: 99%

Receptor-specific interactome as a hub for rapid cue-induced selective translation in axons

Koppers

Cagnetta

Shigeoka

et al. 2019

Preprint

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19During neuronal wiring, extrinsic cues trigger the local translation of specific mRNAs in axons 20 via cell surface receptors. The coupling of ribosomes to receptors has been proposed as a 21 mechanism linking signals to local translation but it is not known how broadly this mechanism 22 operates, nor whether it can selectively regulate mRNA translation. We report that receptor-23 ribosome coupling is employed by multiple guidance cue receptors and this interaction is 24 mRNA-dependent. We find that different receptors bind to distinct sets of mRNAs and RNA-25 binding proteins. Cue stimulation induces rapid dissociation of ribosomes from receptors and 26 the selective translation of receptor-specific mRNAs in retinal axon growth cones. Further, 27we show that receptor-ribosome dissociation and cue-induced selective translation are 28 inhibited by simultaneous exposure to translation-repressive cues, suggesting a novel mode 29 of signal integration. Our findings reveal receptor-specific interactomes and provide a general 30 model for the rapid, localized and selective control of cue-induced translation. 31 Lin and Holt, 2008). Unbiased detection of newly synthesized proteins in the axon 47 compartment has revealed further complexity showing that different guidance cues stimulate 48 the regulation of distinct signature sets of >100 axonal nascent proteins within just 5 mins, 49 many of which are not cytoskeletal-related , Yao et al., 2006, Wu et al., 50 2005. However, the mechanisms underlying the 51 localization and selectivity of translation are unclear. Several mechanisms are known to 52 control different aspects of axonal translation, including microRNA regulation (Bellon et al., 53 2017), mRNA modification (Yu et al., 2018), modulation of the phosphorylation of eukaryotic 54 initiation factors (Cagnetta et al., 2019), RNA-binding protein (RBP) phosphorylation (Sasaki 55 et al., 2010, Lepelletier et al., 2017, Huttelmaier et al., 2005) and receptor-ribosome coupling 56 (Tcherkezian et al. , 2010). The latter is a particularly direct and attractive mechanism to link 57 cue-specific signalling to differential mRNA translation. However, this mechanism has been 58 shown only for the Netrin-1 receptor, deleted in colorectal cancer (DCC), in commissural 59 axon growth cones and HEK293 cells (Tcherkezian et al., 2010) and it is unknown whether 60 receptor-ribosome coupling is a widespread mechanism used by different receptors and in 61 different cell types, and whether it regulates selective local translation. 62 63 Here, we show in retinal ganglion cell (RGC) axon growth cones that receptor-ribosome 64 coupling is used by several different axon guidance receptors (DCC, Neuropilin-1 and 65 Robo2), indicative of a common mechanism. Upon stimulation by specific cues, ribosomes 66 dissociate from their receptors within 2 minutes. Interestingly, the receptor-ribosome 67 interaction is mRNA-dependent, and immunoprecipitation (IP) reveals that distinct receptors 68 associate with specific RNA-binding proteins (RBPs) an...

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“…It impacts both axon regeneration and 6 animal life span. Our work thus places the xbp-1 RNA into the small group of RNAs that act both as coding and non-coding RNAs, sometimes called "coding and non-coding RNAs" 8 (cncRNAs) (Crerar et al, 2019;DeJesus-Hernandez et al, 2011;Ji et al, 2015;Kumari, 2015;Mori et al, 2013;Sampath and Ephrussi, 2016). Such RNAs blur the line between the coding 10 and non-coding RNA worlds and raise the question of how their dual roles are regulated.…”

Section: Roles Of Xbp-1 In Regulating the Neuronal Injury Response 22mentioning

confidence: 99%

“…For example, many miRNAs and circRNAs are processed from intronic regions of pre-mRNAs (Fu, 2014). However, it is less 42 clear whether ncRNAs can be produced from functional, mature mRNAs. Only until recently has it been postulated that coding RNAs can also have non-coding functions (Crerar et al, 2019;44 Kumari, 2015;Sampath and Ephrussi, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…However, it is less 42 clear whether ncRNAs can be produced from functional, mature mRNAs. Only until recently has it been postulated that coding RNAs can also have non-coding functions (Crerar et al, 2019;44 Kumari, 2015;Sampath and Ephrussi, 2016). By characterizing the non-coding function of the xbp-1 locus, our study provides the first example of a ncRNA directly derived from the cleavage 46 3 of a mature mRNA.…”

Section: Introductionmentioning

confidence: 99%

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A functional non-coding RNA is produced fromxbp-1mRNA

Liu

Beaudoin

Davison

et al. 2020

Preprint

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The xbp-1 mRNA encodes the XBP-1 transcription factor, a critical part of the unfolded protein response. Here we report that an RNA fragment produced from xbp-1 mRNA 10 cleavage is a biologically active non-coding RNA (ncRNA) in Caenorhabditis elegans neurons, providing the first example of ncRNA derived from mRNA cleavage. We show that the xbp-1 12 ncRNA is crucial for axon regeneration in vivo, and that it acts independently of the proteincoding function of the xbp-1 transcript. Structural analysis indicates that the function of the xbp-141 ncRNA depends on a single RNA stem; and this stem forms only in the cleaved xbp-1 ncRNA fragment. Disruption of this stem abolishes the non-coding but not coding function of the 16 endogenous xbp-1 transcript. Thus, cleavage of the xbp-1 mRNA bifurcates it into a coding and a non-coding pathway; modulation of the two pathways may allow neurons to fine-tune their 18 response to injury and other stresses.Graphic abstract: 20 22

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Regulation of NGF Signaling by an Axonal Untranslated mRNA

Cited by 40 publications

References 45 publications

Mechanisms and consequences of subcellularRNAlocalization across diverse cell types

Mechanisms and consequences of subcellularRNAlocalization across diverse cell types

Receptor-specific interactome as a hub for rapid cue-induced selective translation in axons

A functional non-coding RNA is produced fromxbp-1mRNA

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