FMRP promotes RNA localization to neuronal projections through interactions between its RGG domain and G-quadruplex RNA sequences

Goering, Raeann; Hudish, Laura I.; Guzman, Bryan B.; Raj, Nisha; Bassell, Gary J.; Russ, Holger A.; Domínguez, Daniel; Taliaferro, J. Matthew

doi:10.7554/elife.52621

Cited by 93 publications

(58 citation statements)

References 86 publications

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“…Dynamic regulation of subcellular RNA localization is critical for biological processes ranging from organismal development to cellular activity 1 7– 6 . While the underlying mechanisms have been found for some transcripts, new aspects of RNA localization regulation continue to arise 7 , 8 . Studies have found that splicing affects RNA localization 9 , 10 .…”

Section: Introductionmentioning

confidence: 99%

Nuclear compartmentalization of TERT mRNA and TUG1 lncRNA is driven by intron retention

et al. 2021

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The spatial partitioning of the transcriptome in the cell is an important form of gene-expression regulation. Here, we address how intron retention influences the spatio-temporal dynamics of transcripts from two clinically relevant genes: TERT (Telomerase Reverse Transcriptase) pre-mRNA and TUG1 (Taurine-Upregulated Gene 1) lncRNA. Single molecule RNA FISH reveals that nuclear TERT transcripts uniformly and robustly retain specific introns. Our data suggest that the splicing of TERT retained introns occurs during mitosis. In contrast, TUG1 has a bimodal distribution of fully spliced cytoplasmic and intron-retained nuclear transcripts. We further test the functionality of intron-retention events using RNA-targeting thiomorpholino antisense oligonucleotides to block intron excision. We show that intron retention is the driving force for the nuclear compartmentalization of these RNAs. For both RNAs, altering this splicing-driven subcellular distribution has significant effects on cell viability. Together, these findings show that stable retention of specific introns can orchestrate spatial compartmentalization of these RNAs within the cell. This process reveals that modulating RNA localization via targeted intron retention can be utilized for RNA-based therapies.

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Section: Introductionmentioning

confidence: 99%

Nuclear compartmentalization of TERT mRNA and TUG1 lncRNA is driven by intron retention

et al. 2021

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“…S10 for FMRP). In this analysis, a shift of the cumulative frequency curve toward the right indicates an up-regulation of targets in the condition of interest, and a leftward shift indicates a down-regulation ( 33 , 34 ). The comparison between FUS targets versus non-target controls shows a minor, albeit significant, right shift (up-regulation) of the cumulative distribution in Ribo- Fus ∆ 14/ ∆ 14 (distance D = 0.05; P = 1.20 × 10 −5 ), while no change was detected in the Ribo- Fus −/− dataset ( D = 0.02; P = 0.26; fig.…”

Section: Resultsmentioning

confidence: 99%

FUS-ALS mutants alter FMRP phase separation equilibrium and impair protein translation

et al. 2021

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FUsed in Sarcoma (FUS) is a multifunctional RNA binding protein (RBP). FUS mutations lead to its cytoplasmic mislocalization and cause the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Here, we use mouse and human models with endogenous ALS-associated mutations to study the early consequences of increased cytoplasmic FUS. We show that in axons, mutant FUS condensates sequester and promote the phase separation of fragile X mental retardation protein (FMRP), another RBP associated with neurodegeneration. This leads to repression of translation in mouse and human FUS-ALS motor neurons and is corroborated in vitro, where FUS and FMRP copartition and repress translation. Last, we show that translation of FMRP-bound RNAs is reduced in vivo in FUS-ALS motor neurons. Our results unravel new pathomechanisms of FUS-ALS and identify a novel paradigm by which mutations in one RBP favor the formation of condensates sequestering other RBPs, affecting crucial biological functions, such as protein translation.

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“…Results from knockdown or overexpression studies are often difficult to interpret, as it is challenging to disentangle phenotypes caused by the pleiotropic functions of proteins required for mRNA transport, such as RBPs and motor proteins. For instance, several RBPs involved in neuronal mRNA transport, such as Fragile X Mental Retardation Protein (FMRP) (Dictenberg et al, 2008 ; Goering et al, 2020 ), are also required for nuclear processes (Shah et al, 2020 ), nuclear mRNA export (Zhang et al, 2007 ; Edens et al, 2019 ), and translation regulation (Feng et al, 1997 ), whereas an mRNP-transporting motor protein like kinesin-1 KIF5 transports a variety of cargoes (Twelvetrees et al, 2010 ; Nakajima et al, 2012 ; Barry et al, 2014 ; Heisler et al, 2014 ; Ruane et al, 2016 ; Henrichs et al, 2020 ; Serra-Marques et al, 2020 ). Hence, analyzing the potential role of an RBP or a motor protein in mRNA transport using knockdowns or overexpressions will inevitably affect multiple cellular processes, making the interpretation of results difficult.…”

Section: Value and Limitations Of Past Approachesmentioning

confidence: 99%

Mammalian Neuronal mRNA Transport Complexes: The Few Knowns and the Many Unknowns

Rodrigues

Grawenhoff

Baumann

et al. 2021

Front. Integr. Neurosci.

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Hundreds of messenger RNAs (mRNAs) are transported into neurites to provide templates for the assembly of local protein networks. These networks enable a neuron to configure different cellular domains for specialized functions. According to current evidence, mRNAs are mostly transported in rather small packages of one to three copies, rarely containing different transcripts. This opens up fascinating logistic problems: how are hundreds of different mRNA cargoes sorted into distinct packages and how are they coupled to and released from motor proteins to produce the observed mRNA distributions? Are all mRNAs transported by the same transport machinery, or are there different adaptors or motors for different transcripts or classes of mRNAs? A variety of often indirect evidence exists for the involvement of proteins in mRNA localization, but relatively little is known about the essential activities required for the actual transport process. Here, we summarize the different types of available evidence for interactions that connect mammalian mRNAs to motor proteins to highlight at which point further research is needed to uncover critical missing links. We further argue that a combination of discovery approaches reporting direct interactions, in vitro reconstitution, and fast perturbations in cells is an ideal future strategy to unravel essential interactions and specific functions of proteins in mRNA transport processes.

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FMRP promotes RNA localization to neuronal projections through interactions between its RGG domain and G-quadruplex RNA sequences

Cited by 93 publications

References 86 publications

Nuclear compartmentalization of TERT mRNA and TUG1 lncRNA is driven by intron retention

Nuclear compartmentalization of TERT mRNA and TUG1 lncRNA is driven by intron retention

FUS-ALS mutants alter FMRP phase separation equilibrium and impair protein translation

Mammalian Neuronal mRNA Transport Complexes: The Few Knowns and the Many Unknowns

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