In Vivo Translatome Profiling in Spinal Muscular Atrophy Reveals a Role for SMN Protein in Ribosome Biology

Bernabò, Paola; Tebaldi, Toma; Groen, Ewout J N; Lane, Fiona M.; Perenthaler, Elena; Mattedi, Francesca; Newbery, Helen; Zhou, Haïyan; Zuccotti, Paola; Potrich, Valentina; Shorrock, Hannah K.; Muntoni, F.; Quattrone, Alessandro; Gillingwater, Thomas H.; Viero, Gabriella

doi:10.1016/j.celrep.2017.10.010

Cited by 100 publications

(129 citation statements)

References 80 publications

(102 reference statements)

Supporting

Mentioning

120

Contrasting

Order By: Relevance

“…However, splicing defects in SMA models are found throughout different tissues, suggesting that SMA pathogenesis relies on additional RNA‐related pathways occurring in neurons. In fact, SMN is a multifunctional protein involved in ribosomal RNA biogenesis, processing of mRNAs, mRNA transport, and translation control …”

Section: Introductionmentioning

confidence: 99%

Impact of RNA–Protein Interaction Modes on Translation Control: The Versatile Multidomain Protein Gemin5

2019

View full text Add to dashboard Cite

The fate of cellular RNAs is largely dependent on their structural conformation, which determines the assembly of ribonucleoprotein (RNP) complexes. Consequently, RNA‐binding proteins (RBPs) play a pivotal role in the lifespan of RNAs. The advent of highly sensitive in cellulo approaches for studying RNPs reveals the presence of unprecedented RNA‐binding domains (RBDs). Likewise, the diversity of the RNA targets associated with a given RBP increases the code of RNA–protein interactions. Increasing evidence highlights the biological relevance of RNA conformation for recognition by specific RBPs and how this mutual interaction affects translation control. In particular, noncanonical RBDs present in proteins such as Gemin5, Roquin‐1, Staufen, and eIF3 eventually determine translation of selective targets. Collectively, recent studies on RBPs interacting with RNA in a structure‐dependent manner unveil new pathways for gene expression regulation, reinforcing the pivotal role of RNP complexes in genome decoding.

show abstract

Section: Introductionmentioning

confidence: 99%

Impact of RNA–Protein Interaction Modes on Translation Control: The Versatile Multidomain Protein Gemin5

2019

View full text Add to dashboard Cite

show abstract

“…Furthermore, a potential role for free RPs in the maintenance of ribosomes in axons has been implicated in a mouse model of spinal muscular atrophy (SMA) (Bernabo et al, 2017).…”

mentioning

confidence: 99%

“…The depletion of the survival motor neuron (SMN) protein, an RNA-binding protein that associates with RP-coding mRNAs (Rage et al, 2013), caused a significant decrease in translation levels of RP-coding mRNAs in mouse motor neuron axons. Although the causal relationship remains uncertain, SMN depletion also leads to a 27% reduction in the number of ribosomes in the axons (Bernabo et al, 2017). These studies prompted us to ask whether axonal ribosomes incorporate locally synthesized RPs to support and/or modify the ribosome function far from the cell body although the limited amount of axonal material make this a technically challenging question to address.…”

mentioning

confidence: 99%

On-site ribosome remodeling by locally synthesized ribosomal proteins in axons

Shigeoka

Koppers

Wong

et al. 2018

Preprint

View full text Add to dashboard Cite

2!SUMMARY Ribosomes are known to be assembled in the nucleolus, yet recent studies have revealed robust enrichment and translation of mRNAs encoding ribosomal proteins (RPs) in axons, far away from neuronal cell bodies. Using subcellular proteomics and live-imaging, we show that locally synthesized RPs incorporate into axonal ribosomes in a nucleolus-independent fashion. We revealed that axonal RP translation is regulated through a novel sequence motif, CUIC, that forms a RNA-loop structure in the region immediately upstream of the initiation codon. Inhibition of axonal CUICregulated RP translation leads to defects in local translation activity and axon branching, demonstrating the physiological relevance of the axonal ribosome remodeling. These results indicate that axonal translation supplies cytoplasmic RPs to maintain/modify local ribosomal function far from the nucleolus. INTRODUCTIONRNA localization and local translation play key roles in the assembly and maintenance of neuronal connections (Campbell and Holt, 2001;Holt and Schuman, 2013;Wu et al., 2005).Recent genome-wide studies on the axonal transcriptome revealed that thousands of mRNAs are localized to the axon. A consistent but unexpected finding of these studies is the robust enrichment of mRNAs that encode ribosomal proteins (RPs), protein components of ribosomes. Axons are long neuronal processes that carry out many vital specific cellular functions far from their cell bodies, including translation, and must therefore maintain their protein synthetic machinery in good order. However, because most eukaryotic ribosome assembly is well known to occur in the nucleolus (Fromont-Racine et al., 2003;Lastick and McConkey, 1976), the physiological function of RP-coding mRNAs in a neuronal subcellular compartment far distant from the nucleus was enigmatic. RP-coding mRNAs have been abundantly detected in axons of a variety of neuron types, such as retinal ganglion cells (RGCs) (Zivraj et al., 2010), sympathetic neurons (Andreassi et al., 2010) and motor ! 5!In this study, we explore intra-ribosomal roles of axonally synthesized RPs using a range of technical approaches including live imaging, in vivo gene knockdown, bioinformatics, nascent protein labeling and mass spectrometry-based proteomics. We found that axonal translation of RPs coordinately peaks at the axon branching stage in RGCs in vivo, and their translation is regulated by a branch-promoting factor, Netrin-1, through a novel loop structure-forming sequence motif, CUIC, that is shared by ~70% of RP-coding mRNAs. Using nascent protein labeling and proteomic mass spectrometry analysis on ribosomes isolated from pure axons, together with live-imaging approaches, we show that axonally synthesized RPs are physically incorporated into axonal ribosomes in a nucleolus-independent fashion. Furthermore, we demonstrate the physiological importance of the axonal ribosome remodeling by showing that inhibition of axonal RP translation leads to a significant decrease in the level of axonal mRNA translation and s...

show abstract

“…In line with our findings, previous studies have reported apparently independent activities of SMN complex members. For example, SMN1 regulates ribosome biology and motor neuron growth 5,44,45 , SMN1's function in motor neurons appears to be independent of snRNP biosynthesis 46 , and SMN1 has a specific role in axonal mRNA regulation and axonogenesis 7,8 . Furthermore, GEMIN3, an RNA helicase, is involved in cell proliferation and microRNA regulation of signal transduction 9 .…”

Section: Discussionmentioning

confidence: 99%

“…The SMN complex consists of nine proteins, however the majority of research on the complex has focused on the characterization of SMN1 and its role in SMA. In addition to its role in the SMN complex, SMN1 plays a role in many other biological processes, including axon growth, mRNA transport, ribosome biology, translational control, and maintaining intracellular homeostasis [5][6][7][8] . Although there is some evidence showing that other SMN complex members, such as GEMIN3 and GEMIN5, also have functions independent of the SMN complex [9][10][11][12] , it remains largely unknown how the other SMN complex members relate to SMA, and whether other members have functions beyond the SMN complex.…”

Section: Introductionmentioning

confidence: 99%

A subset of SMN complex members have a specific role in tissue regeneration via ERBB pathway-mediated proliferation

et al. 2020

View full text Add to dashboard Cite

Spinal muscular atrophy (SMA) is the most common genetic disease in children. SMA is generally caused by mutations in the gene SMN1. The survival of motor neurons (SMN) complex consists of SMN1, Gemins (2-8), and Strap/Unrip. We previously demonstrated smn1 and gemin5 inhibited tissue regeneration in zebrafish. Here we investigated each individual SMN complex member and identified gemin3 as another regeneration-essential gene. These three genes are likely pan-regenerative, since they affect the regeneration of hair cells, liver, and caudal fin. RNA-Seq analysis reveals that smn1, gemin3, and gemin5 are linked to a common set of genetic pathways, including the tp53 and ErbB pathways. Additional studies indicated all three genes facilitate regeneration by inhibiting the ErbB pathway, thereby allowing cell proliferation in the injured neuromasts. This study provides a new understanding of the SMN complex and a potential etiology for SMA and potentially other rare unidentified genetic diseases with similar symptoms.npj Regenerative Medicine (2020) 5:6 ; https://doi.

show abstract

In Vivo Translatome Profiling in Spinal Muscular Atrophy Reveals a Role for SMN Protein in Ribosome Biology

Cited by 100 publications

References 80 publications

Impact of RNA–Protein Interaction Modes on Translation Control: The Versatile Multidomain Protein Gemin5

Impact of RNA–Protein Interaction Modes on Translation Control: The Versatile Multidomain Protein Gemin5

On-site ribosome remodeling by locally synthesized ribosomal proteins in axons

A subset of SMN complex members have a specific role in tissue regeneration via ERBB pathway-mediated proliferation

Contact Info

Product

Resources

About