scholarly journals An alternatively spliced zebrafish jnk1a transcript has an essential and non-redundant role in development of the first heart field derived proximal ventricular chamber

2019 ◽  
Author(s):  
A Santos-Ledo ◽  
S Washer ◽  
T Dhanaseelan ◽  
P Chrystal ◽  
T Papoutsi ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Heart Development ◽  
Planar Cell Polarity ◽  
Cardiac Development ◽  
Single Gene ◽  
Jun Kinase ◽  
Downstream Effectors ◽  
Heart Malformation ◽  
Alternatively Spliced ◽  
First Heart Field

AbstractAlternative splicing is a ubiquitous mechanism for producing different mRNA species from a single gene, resulting in proteomic diversity. Despite potential for regulating embryogenesis, its developmental role remains under-investigated. The Jun kinase (Jnk) genes, considered downstream effectors of the non-canonical Wnt planar cell polarity pathway, utilise extensive and evolutionarily-conserved alternative splicing. Although many PCP members are associated with heart malformation, the role of Jnk genes in cardiac development, and specifically which alternatively spliced transcripts orchestrate these processes, remain unknown. In this study we exploit the jnk1 duplication and subspecialisation found in zebrafish to reveal an essential and non-redundant requirement for jnk1a in cardiac development. We characterise alternatively spliced jnk1a/jnk1b transcripts and demonstrate that hypoplasia of the proximal ventricular component, which corresponds to human hypoplastic left ventricle, can only be rescued by the jnk1a Ex7 Lg transcript. These studies highlight the importance of Jnk signalling and alternative splicing in heart development

scholarly journals Influence of Intron Length on Alternative Splicing of CD44

1998 ◽  
Vol 18 (10) ◽  
pp. 5930-5941 ◽  
Author(s):  
Martyn V. Bell ◽  
Alison E. Cowper ◽  
Marie-Paule Lefranc ◽  
John I. Bell ◽  
Gavin R. Screaton
Keyword(s):  
Alternative Splicing ◽  
Genomic Structure ◽  
Single Gene ◽  
Intron Length ◽  
Protein Isoforms ◽  
Major Influence ◽  
Eukaryotic Genes ◽  
Alternatively Spliced ◽  
Alternatively Spliced Exons

ABSTRACT Although the splicing of transcripts from most eukaryotic genes occurs in a constitutive fashion, some genes can undergo a process of alternative splicing. This is a genetically economical process which allows a single gene to give rise to several protein isoforms by the inclusion or exclusion of sequences into or from the mature mRNA. CD44 provides a unique example; more than 1,000 possible isoforms can be produced by the inclusion or exclusion of a central tandem array of 10 alternatively spliced exons. Certain alternatively spliced exons have been ascribed specific functions; however, independent regulation of the inclusion or skipping of each of these exons would clearly demand an extremely complex regulatory network. Such a network would involve the interaction of many exon-specific trans-acting factors with the pre-mRNA. Therefore, to assess whether the exons are indeed independently regulated, we have examined the alternative exon content of a large number of individual CD44 cDNA isoforms. This analysis shows that the downstream alternatively spliced exons are favored over those lying upstream and that alternative exons are often included in blocks rather than singly. Using a novel in vivo alternative splicing assay, we show that intron length has a major influence upon the alternative splicing of CD44. We propose a kinetic model in which short introns may overcome the poor recognition of alternatively spliced exons. These observations suggest that for CD44, intron length has been exploited in the evolution of the genomic structure to enable tissue-specific patterns of splicing to be maintained.

Alternative splicing can lead to chaos

2015 ◽  
Vol 13 (01) ◽  
pp. 1540003 ◽  
Author(s):  
Vitaly A. Likhoshvai ◽  
Vladislav V. Kogai ◽  
Stanislav I. Fadeev ◽  
Tamara M. Khlebodarova
Keyword(s):  
Alternative Splicing ◽  
Chaotic Dynamics ◽  
Single Gene ◽  
Regulatory Protein ◽  
Genetic System ◽  
Feedback Mechanism ◽  
Regulatory Proteins ◽  
Gene Encoding ◽  
Regulation Type ◽  
Alternatively Spliced

Alternative splicing is a widespread phenomenon in higher eukaryotes, where it serves as a mechanism to increase the functional diversity of proteins. This phenomenon has been described for different classes of proteins, including transcription regulatory proteins. We demonstrated that in the simplest genetic system model the formation of the alternatively spliced isoforms with opposite functions (activators and repressors) could be a cause of transition to chaotic dynamics. Under the simplest genetic system we understand a system consisting of a single gene encoding the structure of a transcription regulatory protein whose expression is regulated by a feedback mechanism. As demonstrated by numerical analysis of the models, if the synthesized isoforms regulate the expression of their own gene acting through different sites and independently of each other, for the generation of chaotic dynamics it is sufficient that the regulatory proteins have a dimeric structure. If regulatory proteins act through one site, the chaotic dynamics is generated in the system only when the repressor protein is either a tetrameric or a higher-dimensional multimer. In this case the activator can be a dimer. It was also demonstrated that if the transcription factor isoforms exhibit either activating or inhibiting activity and are lower-dimensional multimers (< 4), independently of the regulation type the model demonstrates either cyclic or stationary trajectories.

scholarly journals At least 27 alternatively spliced forms of the neural cell adhesion molecule mRNA are expressed during rat heart development.

1991 ◽  
Vol 11 (3) ◽  
pp. 1654-1661 ◽  
Author(s):  
A A Reyes ◽  
S J Small ◽  
R Akeson
Keyword(s):  
Cell Adhesion ◽  
Alternative Splicing ◽  
Adhesion Molecule ◽  
Heart Development ◽  
Rat Heart ◽  
Cell Adhesion Molecule ◽  
Neural Cell Adhesion Molecule ◽  
Neural Cell ◽  
Neural Cell Adhesion ◽  
Alternatively Spliced

The major membrane-associated or transmembrane isoforms of the neural cell adhesion molecule (NCAM) are generated by alternative splicing at the 3' end of the mRNA. Further diversity in NCAM structure is observed in the extracellular region of the polypeptide, where the insertion of additional amino acid residues can result from alternative splicing events occurring at the exon 7-exon 8 and exon 12-exon 13 junctions. Here we report the characterization of tissue-specific patterns of alternative splicing at the exon 12-exon 13 junction by using the polymerase chain reaction. Nine alternatively spliced sequences in rat heart between exon 12 and exon 13 were identified. Each sequence consisted of different combinations of the three small exons (15, 48, and 42 bp in length) and the AAG triplet that make up MSD1, the 108-bp muscle-specific sequence found in human skeletal muscle NCAM (G. Dickson, H.J. Gower, C. H. Barton, H. M. Prentice, V. L. Elsom, S. E. Moore, R. D. Cox, C. Quinn, W. Putt, and F. S. Walsh, Cell 50:1119-1130, 1987). Although the rat equivalent of MSD1 (designated 15+ 48+ 42+ 3+) was detected in all ages of heart examined, it was only one of four or five major splice combinations at any given age. The only alternatively spliced sequence found in the exon 7-exon 8 junction of heart NCAM mRNA was the 30-bp variable alternatively spliced exon previously identified in rat brain. Twenty-seven NCAM forms with distinct sequences were found by analysis of individual NCAM transcripts from postnatal day 1 heart tissue for alternative splicing at the exon 7-exon 8 junction, the exon 12-exon 13 junction and the 3' end. Several combinations of splicing patterns in these three different regions of the gene appeared to be preferentially expressed. The observation that the expression of alternatively spliced forms of NCAM is developmentally regulated suggests a role for NCAM diversity in cardiac development.

Abstract 431: ScaRNAs Regulate Cardiac Differentiation and Development by Fine Tuning the Spliceosome

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Douglas C Bittel ◽  
Brenda Rongish ◽  
Nataliya Kibiryeva ◽  
Michael Filla ◽  
Jennifer Marshall ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Right Ventricle ◽  
Heart Development ◽  
Cardiac Development ◽  
Developmental Regulation ◽  
Cardiac Differentiation ◽  
Fine Tuning ◽  
Cajal Body ◽  
Direct Role ◽  
The Right

Alternative splicing (AS) of mRNA adds diversity to the proteome and precise regulation of AS is essential for proper development. We recently showed that multiple genes critical for heart development are irregularly spliced in the right ventricle of babies with tetralogy of Fallot (TOF). We also observed reduced expression of several noncoding small cajal body associated RNAs (scaRNAs). scaRNAs direct the biochemical modification of spliceosomal RNAs and are essential for the stability and function of the spliceosome. Our results provide compelling evidence for a direct role of scaRNAs in regulating splicing of genes that are critical for heart development. To further explore this novel paradigm of developmental regulation, we analyzed the transcriptome of stem cells as they differentiated to beating cardiomyocytes. We observed significant alternative splicing with respect to timepoint (with Bonferroni correction and fdr of 5%) in 3,165 of 20,301 (15.6%) total genes. Importantly, there were 79 alternatively spliced genes among 213 genes (37.1%) known to be critical for heart development. This is a significant enrichment in the cardiac network genes (p<0.001). Most of the alternative isoforms are known protein coding variants. In addition, we saw changes in expression of several scaRNAs. scaRNA1 is reduced in the right ventricle of children with TOF and we targeted it for knockdown in the quail embryo model system. Preliminary results revealed dramatic alterations in cardiac morphogenesis and embryonic lethality. At higher levels of the antisense oligo, cells appeared to undergo apoptosis, aggregated inappropriately and failed to gastrulate. Lower concentrations resulted in initiation of gastrulation with some cells from the cardiac lineage traversing the embryonic milieu to contribute to the heart and other organs. Interestingly, these cells appeared to lack protrusive phenotypes, and may be passively moved by neighboring groups of non-electroporated motile cells. Taken together, our results suggest scaRNAs are necessary to maintain the fidelity of the spliceosome and thus play an important role in vertebrate heart development. These observations provide additional new insights into regulatory mechanisms underlying cardiac development.

At least 27 alternatively spliced forms of the neural cell adhesion molecule mRNA are expressed during rat heart development

1991 ◽  
Vol 11 (3) ◽  
pp. 1654-1661
Author(s):  
A A Reyes ◽  
S J Small ◽  
R Akeson
Keyword(s):  
Cell Adhesion ◽  
Alternative Splicing ◽  
Adhesion Molecule ◽  
Heart Development ◽  
Rat Heart ◽  
Cell Adhesion Molecule ◽  
Neural Cell Adhesion Molecule ◽  
Neural Cell ◽  
Neural Cell Adhesion ◽  
Alternatively Spliced

The major membrane-associated or transmembrane isoforms of the neural cell adhesion molecule (NCAM) are generated by alternative splicing at the 3' end of the mRNA. Further diversity in NCAM structure is observed in the extracellular region of the polypeptide, where the insertion of additional amino acid residues can result from alternative splicing events occurring at the exon 7-exon 8 and exon 12-exon 13 junctions. Here we report the characterization of tissue-specific patterns of alternative splicing at the exon 12-exon 13 junction by using the polymerase chain reaction. Nine alternatively spliced sequences in rat heart between exon 12 and exon 13 were identified. Each sequence consisted of different combinations of the three small exons (15, 48, and 42 bp in length) and the AAG triplet that make up MSD1, the 108-bp muscle-specific sequence found in human skeletal muscle NCAM (G. Dickson, H.J. Gower, C. H. Barton, H. M. Prentice, V. L. Elsom, S. E. Moore, R. D. Cox, C. Quinn, W. Putt, and F. S. Walsh, Cell 50:1119-1130, 1987). Although the rat equivalent of MSD1 (designated 15+ 48+ 42+ 3+) was detected in all ages of heart examined, it was only one of four or five major splice combinations at any given age. The only alternatively spliced sequence found in the exon 7-exon 8 junction of heart NCAM mRNA was the 30-bp variable alternatively spliced exon previously identified in rat brain. Twenty-seven NCAM forms with distinct sequences were found by analysis of individual NCAM transcripts from postnatal day 1 heart tissue for alternative splicing at the exon 7-exon 8 junction, the exon 12-exon 13 junction and the 3' end. Several combinations of splicing patterns in these three different regions of the gene appeared to be preferentially expressed. The observation that the expression of alternatively spliced forms of NCAM is developmentally regulated suggests a role for NCAM diversity in cardiac development.

scholarly journals Exploring the functional impact of alternative splicing on human protein isoforms using available annotation sources

2019 ◽  
Vol 20 (5) ◽  
pp. 1754-1768 ◽  
Author(s):  
Dinanath Sulakhe ◽  
Mark D’Souza ◽  
Sheng Wang ◽  
Sandhya Balasubramanian ◽  
Prashanth Athri ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Contextual Information ◽  
Single Gene ◽  
Cellular Responses ◽  
Protein Isoforms ◽  
Modeling And Analysis ◽  
The Public ◽  
Alternatively Spliced ◽  
Cellular Pathways ◽  
Genome Analyses

Abstract In recent years, the emphasis of scientific inquiry has shifted from whole-genome analyses to an understanding of cellular responses specific to tissue, developmental stage or environmental conditions. One of the central mechanisms underlying the diversity and adaptability of the contextual responses is alternative splicing (AS). It enables a single gene to encode multiple isoforms with distinct biological functions. However, to date, the functions of the vast majority of differentially spliced protein isoforms are not known. Integration of genomic, proteomic, functional, phenotypic and contextual information is essential for supporting isoform-based modeling and analysis. Such integrative proteogenomics approaches promise to provide insights into the functions of the alternatively spliced protein isoforms and provide high-confidence hypotheses to be validated experimentally. This manuscript provides a survey of the public databases supporting isoform-based biology. It also presents an overview of the potential global impact of AS on the human canonical gene functions, molecular interactions and cellular pathways.

scholarly journals Deep Splicing Code: Classifying Alternative Splicing Events Using Deep Learning

Genes ◽  
2019 ◽  
Vol 10 (8) ◽  
pp. 587 ◽  
Author(s):  
Zakaria Louadi ◽  
Mhaned Oubounyt ◽  
Hilal Tayara ◽  
Kil To Chong
Keyword(s):  
Deep Learning ◽  
Alternative Splicing ◽  
Computational Models ◽  
Genomic Sequence ◽  
Single Gene ◽  
Splicing Factors ◽  
Local Characteristics ◽  
Alternatively Spliced ◽  
Exon Junctions ◽  
Alternatively Spliced Exons

Alternative splicing (AS) is the process of combining different parts of the pre-mRNA to produce diverse transcripts and eventually different protein products from a single gene. In computational biology field, researchers try to understand AS behavior and regulation using computational models known as “Splicing Codes”. The final goal of these algorithms is to make an in-silico prediction of AS outcome from genomic sequence. Here, we develop a deep learning approach, called Deep Splicing Code (DSC), for categorizing the well-studied classes of AS namely alternatively skipped exons, alternative 5’ss, alternative 3’ss, and constitutively spliced exons based only on the sequence of the exon junctions. The proposed approach significantly improves the prediction and the obtained results reveal that constitutive exons have distinguishable local characteristics from alternatively spliced exons. Using the motif visualization technique, we show that the trained models learned to search for competitive alternative splice sites as well as motifs of important splicing factors with high precision. Thus, the proposed approach greatly expands the opportunities to improve alternative splicing modeling. In addition, a web-server for AS events prediction has been developed based on the proposed method and made available at https://home.jbnu.ac.kr/NSCL/dsc.htm.

scholarly journals Alternative splicing and the evolution of phenotypic novelty

2017 ◽  
Vol 372 (1713) ◽  
pp. 20150474 ◽  
Author(s):  
Stephen J. Bush ◽  
Lu Chen ◽  
Jaime M. Tovar-Corona ◽  
Araxi O. Urrutia
Keyword(s):  
Alternative Splicing ◽  
Gene Duplication ◽  
Single Gene ◽  
Morphological Diversity ◽  
Cell Types ◽  
Evolutionary Diversification ◽  
Population Sizes ◽  
Alternatively Spliced ◽  
Alternative Splicing Events ◽  
Multicellular Organisms

Alternative splicing, a mechanism of post-transcriptional RNA processing whereby a single gene can encode multiple distinct transcripts, has been proposed to underlie morphological innovations in multicellular organisms. Genes with developmental functions are enriched for alternative splicing events, suggestive of a contribution of alternative splicing to developmental programmes. The role of alternative splicing as a source of transcript diversification has previously been compared to that of gene duplication, with the relationship between the two extensively explored. Alternative splicing is reduced following gene duplication with the retention of duplicate copies higher for genes which were alternatively spliced prior to duplication. Furthermore, and unlike the case for overall gene number, the proportion of alternatively spliced genes has also increased in line with the evolutionary diversification of cell types, suggesting alternative splicing may contribute to the complexity of developmental programmes. Together these observations suggest a prominent role for alternative splicing as a source of functional innovation. However, it is unknown whether the proliferation of alternative splicing events indeed reflects a functional expansion of the transcriptome or instead results from weaker selection acting on larger species, which tend to have a higher number of cell types and lower population sizes. This article is part of the themed issue ‘Evo-devo in the genomics era, and the origins of morphological diversity’.

scholarly journals Myocardium-Specific Deletion of Rac1 Causes Ventricular Noncompaction and Outflow Tract Defects

2021 ◽  
Vol 8 (3) ◽  
pp. 29
Author(s):  
Carmen Leung ◽  
Anish Engineer ◽  
Mella Y. Kim ◽  
Xiangru Lu ◽  
Qingping Feng
Keyword(s):  
Heart Development ◽  
Planar Cell Polarity ◽  
Cardiac Development ◽  
Current Knowledge ◽  
Ventricular Myocardium ◽  
Double Outlet Right Ventricle ◽  
Left Ventricular ◽  
Small Gtpase ◽  
Ventricular Noncompaction ◽  
Specific Deletion

Background: Left ventricular noncompaction (LVNC) is a cardiomyopathy that can lead to arrhythmias, embolic events and heart failure. Despite our current knowledge of cardiac development, the mechanisms underlying noncompaction of the ventricular myocardium are still poorly understood. The small GTPase Rac1 acts as a crucial regulator of numerous developmental events. The present study aimed to investigate the cardiomyocyte specific role of Rac1 in embryonic heart development. Methods and Results: The Nkx2.5-Cre transgenic mice were crossed with Rac1f/f mice to generate mice with a cardiomyocyte specific deletion of Rac1 (Rac1Nkx2.5) during heart development. Embryonic Rac1Nkx2.5 hearts at E12.5–E18.5 were collected for histological analysis. Overall, Rac1Nkx2.5 hearts displayed a bifid apex, along with hypertrabeculation and a thin compact myocardium. Rac1Nkx2.5 hearts also exhibited ventricular septal defects (VSDs) and double outlet right ventricle (DORV) or overriding aorta. Cardiomyocytes had a rounded morphology and were highly disorganized, and the myocardial expression of Scrib, a planar cell polarity protein, was reduced in Rac1Nkx2.5 hearts. In addition, cell proliferation rate was significantly decreased in the Rac1Nkx2.5 ventricular myocardium at E9.5. Conclusions: Rac1 deficiency in the myocardium impairs cardiomyocyte elongation and organization, and proliferative growth of the heart. A spectrum of CHDs arises in Rac1Nkx2.5 hearts, implicating Rac1 signaling in the ventricular myocardium as a crucial regulator of OFT alignment, along with compact myocardium growth and development.

Linking transcription, RNA polymerase II elongation and alternative splicing

2020 ◽  
Vol 477 (16) ◽  
pp. 3091-3104 ◽  
Author(s):  
Luciana E. Giono ◽  
Alberto R. Kornblihtt
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Rna Polymerase Ii ◽  
Environmental Changes ◽  
Transcription Elongation ◽  
Single Gene ◽  
Regulation Of Gene Expression ◽  
Regulation Of Transcription ◽  
Stepping Stones ◽  
Eukaryotic Transcription

Gene expression is an intricately regulated process that is at the basis of cell differentiation, the maintenance of cell identity and the cellular responses to environmental changes. Alternative splicing, the process by which multiple functionally distinct transcripts are generated from a single gene, is one of the main mechanisms that contribute to expand the coding capacity of genomes and help explain the level of complexity achieved by higher organisms. Eukaryotic transcription is subject to multiple layers of regulation both intrinsic — such as promoter structure — and dynamic, allowing the cell to respond to internal and external signals. Similarly, alternative splicing choices are affected by all of these aspects, mainly through the regulation of transcription elongation, making it a regulatory knob on a par with the regulation of gene expression levels. This review aims to recapitulate some of the history and stepping-stones that led to the paradigms held today about transcription and splicing regulation, with major focus on transcription elongation and its effect on alternative splicing.

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