scholarly journals The Fine Art of Writing a Message: RNA Metabolism in the Shaping and Remodeling of the Nervous System

2021 ◽  
Vol 14 ◽  
Author(s):  
María Landínez-Macías ◽  
Olivier Urwyler
Keyword(s):  
Nervous System ◽  
Binding Proteins ◽  
Neuronal Development ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Axon Growth ◽  
Rna Metabolism ◽  
Nervous System Development ◽  
Protein Isoforms ◽  
Growth Guidance

Neuronal morphogenesis, integration into circuits, and remodeling of synaptic connections occur in temporally and spatially defined steps. Accordingly, the expression of proteins and specific protein isoforms that contribute to these processes must be controlled quantitatively in time and space. A wide variety of post-transcriptional regulatory mechanisms, which act on pre-mRNA and mRNA molecules contribute to this control. They are thereby critically involved in physiological and pathophysiological nervous system development, function, and maintenance. Here, we review recent findings on how mRNA metabolism contributes to neuronal development, from neural stem cell maintenance to synapse specification, with a particular focus on axon growth, guidance, branching, and synapse formation. We emphasize the role of RNA-binding proteins, and highlight their emerging roles in the poorly understood molecular processes of RNA editing, alternative polyadenylation, and temporal control of splicing, while also discussing alternative splicing, RNA localization, and local translation. We illustrate with the example of the evolutionary conserved Musashi protein family how individual RNA-binding proteins are, on the one hand, acting in different processes of RNA metabolism, and, on the other hand, impacting multiple steps in neuronal development and circuit formation. Finally, we provide links to diseases that have been associated with the malfunction of RNA-binding proteins and disrupted post-transcriptional regulation.

Multiple Roles of RNA Regulatory Factors in Neuronal Development and Function in C. elegans

2020 ◽  
Author(s):  
Matthew G. Andrusiak ◽  
Yishi Jin
Keyword(s):  
Nervous System ◽  
Cell Biology ◽  
Molecular Mechanisms ◽  
Neuronal Development ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Model Organism ◽  
Nervous System Development ◽  
Forward Genetics ◽  
C Elegans

Recent evidence has highlighted the dynamic nature of mRNA regulation, particularly in the nervous system, from complex pre-mRNA processing to long-range transport and long-term storage of mature mRNAs. In accordance with the importance for mRNA-mediated regulation of nervous system development and maintenance, various mutations in RNA-binding proteins are associated with a range of human disorders. C. elegans express many RNA-binding factors that have human orthologs and perform similar biochemical functions. This chapter focuses on the research using C. elegans to dissect molecular mechanisms involving mRNA-mediated pathways. It highlights the key approaches and findings that integrate genetic and genomic studies in the nervous system. The analyses of genetic mutants, primarily using forward genetics, offer functional insights for genes important for neuronal development, synaptic transmission, and neuronal repair. In combination with single-neuron cell biology and cell-type genomics, the knowledge learned from this model organism has continued to lead to ground-breaking discoveries.

Drosophila Shep and C. elegans SUP-26 are RNA-binding proteins that play diverse roles in nervous system development

2015 ◽  
Vol 225 (6) ◽  
pp. 319-330 ◽  
Author(s):  
Logan T. Schachtner ◽  
Ismail E. Sola ◽  
Daniel Forand ◽  
Simona Antonacci ◽  
Adam J. Postovit ◽  
...  
Keyword(s):  
Nervous System ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
System Development ◽  
Nervous System Development ◽  
C Elegans

Dorsal-ventral patterning and differentiation of noggin-induced neural tissue in the absence of mesoderm

Development ◽  
1995 ◽  
Vol 121 (6) ◽  
pp. 1927-1935 ◽  
Author(s):  
A.K. Knecht ◽  
P.J. Good ◽  
I.B. Dawid ◽  
R.M. Harland
Keyword(s):  
Nervous System ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Neural Tissue ◽  
Expression Domain ◽  
Xenopus Development ◽  
Dorsal Mesoderm

In Xenopus development, dorsal mesoderm is thought to play a key role in both induction and patterning of the nervous system. Previously, we identified a secreted factor, noggin, which is expressed in dorsal mesoderm and which can mimic that tissue's neural-inducing activity, without inducing mesoderm. Here the neural tissue induced in ectodermal explants by noggin is further characterized using four neural-specific genes: two putative RNA-binding proteins, nrp-1 and etr-1; the synaptobrevin sybII; and the lipocalin cpl-1. First we determine the expression domain of each gene during embryogenesis. Then we analyze expression of these genes in noggin-treated explants. All markers, including the differentiated marker sybII, are expressed in noggin-induced neural tissue. Furthermore, cpl-1, a marker of dorsal brain, and etr-1, a marker absent in much of the dorsal forebrain, are expressed in non-overlapping territories within these explants. We conclude that the despite the absence of mesoderm, noggin-induced neural tissue shows considerable differentiation and organization, which may represent dorsal-ventral patterning of the forebrain.

scholarly journals RNA Is a Double-Edged Sword in ALS Pathogenesis

2021 ◽  
Vol 15 ◽  
Author(s):  
Benjamin L. Zaepfel ◽  
Jeffrey D. Rothstein
Keyword(s):  
Motor Neurons ◽  
Cortical Neurons ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Rna Metabolism ◽  
Small Subset ◽  
Toxic Rna ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease that affects upper and lower motor neurons. Familial ALS accounts for a small subset of cases (<10–15%) and is caused by dominant mutations in one of more than 10 known genes. Multiple genes have been causally or pathologically linked to both ALS and frontotemporal dementia (FTD). Many of these genes encode RNA-binding proteins, so the role of dysregulated RNA metabolism in neurodegeneration is being actively investigated. In addition to defects in RNA metabolism, recent studies provide emerging evidence into how RNA itself can contribute to the degeneration of both motor and cortical neurons. In this review, we discuss the roles of altered RNA metabolism and RNA-mediated toxicity in the context of TARDBP, FUS, and C9ORF72 mutations. Specifically, we focus on recent studies that describe toxic RNA as the potential initiator of disease, disease-associated defects in specific RNA metabolism pathways, as well as how RNA-based approaches can be used as potential therapies. Altogether, we highlight the importance of RNA-based investigations into the molecular progression of ALS, as well as the need for RNA-dependent structural studies of disease-linked RNA-binding proteins to identify clear therapeutic targets.

scholarly journals Roles of Organellar RNA-Binding Proteins in Plant Growth, Development, and Abiotic Stress Responses

2020 ◽  
Vol 21 (12) ◽  
pp. 4548 ◽  
Author(s):  
Kwanuk Lee ◽  
Hunseung Kang
Keyword(s):  
Abiotic Stress ◽  
Plant Growth ◽  
Stress Responses ◽  
Translational Control ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Rna Metabolism ◽  
Functional Roles ◽  
Growth Development

Organellar gene expression (OGE) in chloroplasts and mitochondria is primarily modulated at post-transcriptional levels, including RNA processing, intron splicing, RNA stability, editing, and translational control. Nucleus-encoded Chloroplast or Mitochondrial RNA-Binding Proteins (nCMRBPs) are key regulatory factors that are crucial for the fine-tuned regulation of post-transcriptional RNA metabolism in organelles. Although the functional roles of nCMRBPs have been studied in plants, their cellular and physiological functions remain largely unknown. Nevertheless, existing studies that have characterized the functions of nCMRBP families, such as chloroplast ribosome maturation and splicing domain (CRM) proteins, pentatricopeptide repeat (PPR) proteins, DEAD-Box RNA helicase (DBRH) proteins, and S1-domain containing proteins (SDPs), have begun to shed light on the role of nCMRBPs in plant growth, development, and stress responses. Here, we review the latest research developments regarding the functional roles of organellar RBPs in RNA metabolism during growth, development, and abiotic stress responses in plants.

scholarly journals The CELF Family of RNA Binding Proteins Is Implicated in Cell-Specific and Developmentally Regulated Alternative Splicing

2001 ◽  
Vol 21 (4) ◽  
pp. 1285-1296 ◽  
Author(s):  
Andrea N. Ladd ◽  
Nicolas Charlet-B. ◽  
Thomas A. Cooper
Keyword(s):  
Alternative Splicing ◽  
Heart Development ◽  
Binding Proteins ◽  
Rna Binding ◽  
Striated Muscle ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Protein Isoforms ◽  
Developmentally Regulated ◽  
Exon Inclusion

ABSTRACT Alternative splicing of cardiac troponin T (cTNT) exon 5 undergoes a developmentally regulated switch such that exon inclusion predominates in embryonic, but not adult, striated muscle. We previously described four muscle-specific splicing enhancers (MSEs) within introns flanking exon 5 in chicken cTNT that are both necessary and sufficient for exon inclusion in embryonic muscle. We also demonstrated that CUG-binding protein (CUG-BP) binds a conserved CUG motif within a human cTNT MSE and positively regulates MSE-dependent exon inclusion. Here we report that CUG-BP is one of a novel family of developmentally regulated RNA binding proteins that includes embryonically lethal abnormal vision-type RNA binding protein 3 (ETR-3). This family, which we call CELF proteins for CUG-BP- and ETR-3-like factors, specifically bound MSE-containing RNAs in vitro and activated MSE-dependent exon inclusion of cTNT minigenes in vivo. The expression of two CELF proteins is highly restricted to brain. CUG-BP, ETR-3, and CELF4 are more broadly expressed, and expression is developmentally regulated in striated muscle and brain. Changes in the level of expression and isoforms of ETR-3 in two different developmental systems correlated with regulated changes in cTNT splicing. A switch from cTNT exon skipping to inclusion tightly correlated with induction of ETR-3 protein expression during differentiation of C2C12 myoblasts. During heart development, the switch in cTNT splicing correlated with a transition in ETR-3 protein isoforms. We propose that ETR-3 is a major regulator of cTNT alternative splicing and that the CELF family plays an important regulatory role in cell-specific alternative splicing during normal development and disease.

scholarly journals Middle-down proteomics reveals dense sites of methylation and phosphorylation in arginine-rich RNA-binding proteins

2019 ◽  
Author(s):  
Sean R. Kundinger ◽  
Isaac Bishof ◽  
Eric B. Dammer ◽  
Duc M. Duong ◽  
Nicholas T. Seyfried
Keyword(s):  
Binding Proteins ◽  
Electron Transfer Dissociation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Rna Metabolism ◽  
Hek293 Cells ◽  
Motif Analysis ◽  
Proteomic Approach ◽  
Nuclear Extracts ◽  
And Function

AbstractArginine (Arg)-rich RNA-binding proteins play an integral role in RNA metabolism. Post-translational modifications (PTMs) within Arg-rich domains, such as phosphorylation and methylation, regulate multiple steps in RNA metabolism. However, the identification of PTMs within Arg-rich domains with complete trypsin digestion is extremely challenging due to the high density of Arg residues within these proteins. Here, we report a middle-down proteomic approach coupled with electron transfer dissociation (ETD) mass spectrometry to map previously unknown sites of phosphorylation and methylation within the Arg-rich domains of U1-70K and structurally similar RNA-binding proteins from nuclear extracts of HEK293 cells. Remarkably, the Arg-rich domains in RNA-binding proteins are densely modified by methylation and phosphorylation compared with the remainder of the proteome, with di-methylation and phosphorylation favoring RSRS motifs. Although they favor a common motif, analysis of combinatorial PTMs within RSRS motifs indicate that phosphorylation and methylation do not often co-occur, suggesting they may functionally oppose one another. Collectively, these findings suggest that the level of PTMs within Arg-rich domains may be among the highest in the proteome, and a possible unexplored regulator of RNA metabolism. These data also serve as a resource to facilitate future mechanistic studies of the role of PTMs in RNA-binding protein structure and function.BriefsMiddle-down proteomics reveals arginine-rich RNA-binding proteins contain many sites of methylation and phosphorylation.

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