Binding proteins for mRNA localization and local translation, and their dysfunction in genetic neurological disease

2004 ◽  
Vol 14 (5) ◽  
pp. 574-581 ◽  
Author(s):  
Gary J Bassell ◽  
Sofija Kelic
Keyword(s):  
Neurological Disease ◽  
Binding Proteins ◽  
Mrna Localization ◽  
Local Translation

scholarly journals Cataloguing and Selection of mRNAs Localized to Dendrites in Neurons and Regulated by RNA-Binding Proteins in RNA Granules

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 167 ◽  
Author(s):  
Ohashi ◽  
Shiina
Keyword(s):  
Synaptic Plasticity ◽  
Cell Fate ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Memory Formation ◽  
Long Term Memory ◽  
Local Translation ◽  
Rna Granules

Spatiotemporal translational regulation plays a key role in determining cell fate and function. Specifically, in neurons, local translation in dendrites is essential for synaptic plasticity and long-term memory formation. To achieve local translation, RNA-binding proteins in RNA granules regulate target mRNA stability, localization, and translation. To date, mRNAs localized to dendrites have been identified by comprehensive analyses. In addition, mRNAs associated with and regulated by RNA-binding proteins have been identified using various methods in many studies. However, the results obtained from these numerous studies have not been compiled together. In this review, we have catalogued mRNAs that are localized to dendrites and are associated with and regulated by the RNA-binding proteins fragile X mental retardation protein (FMRP), RNA granule protein 105 (RNG105, also known as Caprin1), Ras-GAP SH3 domain binding protein (G3BP), cytoplasmic polyadenylation element binding protein 1 (CPEB1), and staufen double-stranded RNA binding proteins 1 and 2 (Stau1 and Stau2) in RNA granules. This review provides comprehensive information on dendritic mRNAs, the neuronal functions of mRNA-encoded proteins, the association of dendritic mRNAs with RNA-binding proteins in RNA granules, and the effects of RNA-binding proteins on mRNA regulation. These findings provide insights into the mechanistic basis of protein-synthesis-dependent synaptic plasticity and memory formation and contribute to future efforts to understand the physiological implications of local regulation of dendritic mRNAs in neurons.

scholarly journals The crystal structure of Staufen1 in complex with a physiological RNA sheds light on substrate selectivity

2018 ◽  
Vol 1 (5) ◽  
pp. e201800187 ◽  
Author(s):  
Daniela Lazzaretti ◽  
Lina Bandholz-Cajamarca ◽  
Christiane Emmerich ◽  
Kristina Schaaf ◽  
Claire Basquin ◽  
...  
Keyword(s):  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Structural Information ◽  
Target Selection ◽  
Mrna Localization ◽  
In Vitro Binding ◽  
Vitro Binding

During mRNA localization, RNA-binding proteins interact with specific structured mRNA localization motifs. Although several such motifs have been identified, we have limited structural information on how these interact with RNA-binding proteins. Staufen proteins bind structured mRNA motifs through dsRNA-binding domains (dsRBD) and are involved in mRNA localization in Drosophila and mammals. We solved the structure of two dsRBDs of human Staufen1 in complex with a physiological dsRNA sequence. We identified interactions between the dsRBDs and the RNA sugar–phosphate backbone and direct contacts of conserved Staufen residues to RNA bases. Mutating residues mediating nonspecific backbone interactions only affected Staufen function in Drosophila when in vitro binding was severely reduced. Conversely, residues involved in base-directed interactions were required in vivo even when they minimally affected in vitro binding. Our work revealed that Staufen can read sequence features in the minor groove of dsRNA and suggests that these influence target selection in vivo.

scholarly journals CMTr cap-adjacent 2’-O-ribose mRNA methyltransferases are required for reward learning and mRNA localization to synapses

2021 ◽  
Author(s):  
Irmgard U. Haussmann ◽  
Yanying Wu ◽  
Mohanakarthik P. Nallasivan ◽  
Nathan Archer ◽  
Zsuzsanna Bodi ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Cell Adhesion ◽  
Mushroom Body ◽  
Double Mutant ◽  
Mrna Localization ◽  
Signaling Molecules ◽  
Reward Learning ◽  
Local Translation ◽  
Viral Mrnas ◽  
Conditional Expression

AbstractCap-adjacent nucleotides of animal, protist and viral mRNAs can be dynamically O-methylated at the 2’ position of the ribose (cOMe). The functions of cOMe in animals, however, remain unknown. Here we show that the two cap methyltransferases (CMTr1 and CMTr2) of Drosophila can methylate the ribose of the first nucleotide in mRNA. Double-mutant flies lack cOMe but are viable. Consistent with prominent neuronal expression, they have a reward learning defect that can be rescued by conditional expression in mushroom body neurons before training. Among CMTr targets are cell adhesion and signaling molecules relevant for learning and cOMe is required for local translation of mRNAs at synapses. Hence, our study reveals a mechanism to co-transcriptionally prime mRNAs by cOMe for localized protein synthesis at synapses.

scholarly journals Subcellular sequencing of single neurons reveals the dendritic transcriptome of GABAergic interneurons

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Julio D Perez ◽  
Susanne tom Dieck ◽  
Beatriz Alvarez-Castelao ◽  
Georgi Tushev ◽  
Ivy CW Chan ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Large Population ◽  
Cell Types ◽  
Mrna Localization ◽  
Gabaergic Neurons ◽  
Local Translation ◽  
Single Neurons ◽  
Cell Type ◽  
Cell Type Specific

Although mRNAs are localized in the processes of excitatory neurons, it is still unclear whether interneurons also localize a large population of mRNAs. In addition, the variability in the localized mRNA population within and between cell-types is unknown. Here we describe the unbiased transcriptomic characterization of the subcellular compartments of hundreds of single neurons. We separately profiled the dendritic and somatic transcriptomes of individual rat hippocampal neurons and investigated mRNA abundances in the soma and dendrites of single glutamatergic and GABAergic neurons. We found that, like their excitatory counterparts, interneurons contain a rich repertoire of ~4000 mRNAs. We observed more cell type-specific features among somatic transcriptomes than their associated dendritic transcriptomes. Finally, using cell-type specific metabolic labelling of isolated neurites, we demonstrated that the processes of Glutamatergic and, notably, GABAergic neurons were capable of local translation, suggesting mRNA localization and local translation is a general property of neurons.

scholarly journals Subcellular mRNA localization and local translation of Arhgap11a in radial glial cells regulates cortical development

2020 ◽  
Author(s):  
Louis-Jan Pilaz ◽  
Kaumudi Joshi ◽  
Jing Liu ◽  
Yuji Tsunekawa ◽  
Fernando Alsina ◽  
...  
Keyword(s):  
Glial Cells ◽  
Mrna Localization ◽  
Local Translation ◽  
Control Of Gene Expression ◽  
Radial Glial Cells ◽  
Rhoa Activity ◽  
Cis Element ◽  
Control Brain ◽  
Radial Glial ◽  
Cellular Compartments

mRNA localization and local translation enable exquisite spatial and temporal control of gene expression, particularly in highly polarized and elongated cells. These features are especially prominent in radial glial cells (RGCs), which serve as neural and glial precursors of the developing cerebral cortex, and scaffolds for migrating neurons. Yet the mechanisms by which distinct sub-cellular compartments of RGCs accomplish their diverse functions are poorly understood. Here, we demonstrate that subcellular RNA localization and translation of the RhoGAP Arhgap11a controls RGC morphology and mediates cortical cytoarchitecture. Arhgap11a mRNA and protein exhibit conserved localization to RGC basal structures in mice and humans, conferred by a 5′UTR cis-element. Proper RGC morphology relies upon active Arhgap11a mRNA transport and localization to basal structures, where ARHGAP11A is locally synthesized. Thus, RhoA activity is spatially and acutely activated via local translation in RGCs to promote neuron positioning and cortical cytoarchitecture. Altogether, our study demonstrates that mRNA localization and local translation mediate compartmentalization of neural progenitor functions to control brain development.

RNA-binding proteins in neurological disease

2012 ◽  
Vol 1462 ◽  
pp. 1-2 ◽  
Author(s):  
Fen-Biao Gao ◽  
J. Paul Taylor
Keyword(s):  
Neurological Disease ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins

scholarly journals A localization screen reveals translation factories and widespread co-translational RNA targeting

2020 ◽  
Author(s):  
Racha Chouaib ◽  
Adham Safieddine ◽  
Xavier Pichon ◽  
Arthur Imbert ◽  
Oh Sung Kwon ◽  
...  
Keyword(s):  
Protein Metabolism ◽  
Mrna Localization ◽  
Local Translation ◽  
Mature Protein ◽  
Control Of Gene Expression ◽  
Spatial Control ◽  
Rna Targeting ◽  
Cycle Dependent ◽  
High Degree ◽  
Quantitation Of Mrna

SummaryLocal translation allows a spatial control of gene expression. Here, we performed a dual protein/mRNA localization screen, using smFISH on 523 human cell lines expressing GFP-tagged genes. A total of 32 mRNAs displayed specific cytoplasmic localizations, and we observed local translation at unexpected locations, including cytoplasmic protrusions, cell edges, endosomes, Golgi, the nuclear envelope and centrosomes, the latter being cell cycle dependent. Quantitation of mRNA distribution and automatic pattern classification revealed a high degree of localization heterogeneity between cells. Surprisingly, mRNA localization frequently required ongoing translation, indicating widespread co-translational RNA targeting. Interestingly, while P-body accumulation was frequent (15 mRNAs), four mRNAs accumulated in foci that were distinct structures. These foci lacked the mature protein, but nascent polypeptide imaging showed that they were specialized translation factories. For β-catenin, foci formation was regulated by Wnt, relied on APC-dependent polysome aggregation, and led to nascent protein degradation. Thus, translation factories uniquely regulate nascent protein metabolism and create a fine granular compartmentalization of translation.

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