PUBLICATION

Alternative splicing of jnk1a in zebrafish determines first heart field ventricular cardiomyocyte numbers through modulation of hand2 expression

Authors
Santos-Ledo, A., Washer, S., Dhanaseelan, T., Eley, L., Alqatani, A., Chrystal, P.W., Papoutsi, T., Henderson, D.J., Chaudhry, B.
ID
ZDB-PUB-200519-3
Date
2020
Source
PLoS Genetics   16: e1008782 (Journal)
Registered Authors
Chaudhry, Bill
Keywords
none
MeSH Terms
  • Cell Count
  • Myocytes, Cardiac/cytology
  • Myocytes, Cardiac/metabolism
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
  • Heart Ventricles/cytology*
  • Heart Ventricles/embryology
  • Heart Ventricles/metabolism
  • Mitogen-Activated Protein Kinase 8/genetics*
  • Mitogen-Activated Protein Kinase 8/metabolism
  • Basic Helix-Loop-Helix Transcription Factors/genetics
  • Basic Helix-Loop-Helix Transcription Factors/metabolism*
  • Cells, Cultured
  • Zebrafish/embryology*
  • Zebrafish/genetics
  • Zebrafish/metabolism
  • Animals
  • Exons
  • Alternative Splicing
  • Gene Expression Regulation, Developmental
(all 20)
PubMed
32421721 Full text @ PLoS Genet.
Abstract
The planar cell polarity pathway is required for heart development and whilst the functions of most pathway members are known, the roles of the jnk genes in cardiac morphogenesis remain unknown as mouse mutants exhibit functional redundancy, with early embryonic lethality of compound mutants. In this study zebrafish were used to overcome early embryonic lethality in mouse models and establish the requirement for Jnk in heart development. Whole mount in-situ hybridisation and RT-PCR demonstrated that evolutionarily conserved alternative spliced jnk1a and jnk1b transcripts were expressed in the early developing heart. Maternal zygotic null mutant zebrafish lines for jnk1a and jnk1b, generated using CRISPR-Cas9, revealed a requirement for jnk1a in formation of the proximal, first heart field (FHF)-derived portion of the cardiac ventricular chamber. Rescue of the jnk1a mutant cardiac phenotype was only possible by injection of the jnk1a EX7 Lg alternatively spliced transcript. Analysis of mutants indicated that there was a reduction in the size of the hand2 expression field in jnk1a mutants which led to a specific reduction in FHF ventricular cardiomyocytes within the anterior lateral plate mesoderm. Moreover, the jnk1a mutant ventricular defect could be rescued by injection of hand2 mRNA. This study reveals a novel and critical requirement for Jnk1 in heart development and highlights the importance of alternative splicing in vertebrate cardiac morphogenesis. Genetic pathways functioning through jnk1 may be important in human heart malformations with left ventricular hypoplasia.
Genes / Markers
Figures
Figure Gallery (13 images) / 2
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
mapk8an2/n2 (AB)standard conditionsPrim-5
mapk8an2/n2 (AB)standard conditionsPrim-5
mapk8an2/n2 (AB)standard conditionsPrim-5
mapk8an2/n2 (AB)standard conditionsPrim-5
mapk8an2/n2 (AB)standard conditionsLong-pec
mapk8an2/n2 (AB)standard conditionsLong-pec
mapk8an2/n2 (AB)standard conditionsLong-pec
mapk8an2/n2 (AB)standard conditionsProtruding-mouth
mapk8an2/n2 (AB)standard conditionsProtruding-mouth
mapk8an2/n2 (AB)standard conditionsProtruding-mouth
1 - 10 of 38
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
n2
    		Small Deletion
    n3
      		Small Deletion
      twu34TgTransgenic Insertion
        1 - 3 of 3
        Show
        Human Disease / Model
        No data available
        Sequence Targeting Reagents
        Target Reagent Reagent Type
        mapk8aCRISPR1-mapk8aCRISPR
        mapk8bCRISPR1-mapk8bCRISPR
        1 - 2 of 2
        Show
        Fish
        Fish
        AB
        mapk8an2/n2 (AB)
        mapk8an2/n2; mapk8bn3/n3 (AB)
        mapk8an2/n2; mapk8bn3/n3; twu34Tg (AB)
        mapk8an2/n2; twu34Tg (AB)
        mapk8bn3/n3 (AB)
        mapk8bn3/n3; twu34Tg (AB)
        WT
        1 - 8 of 8
        Show
        Antibodies
        Orthology
        Gene Orthology
        mapk8a
        mapk8b
        1 - 2 of 2
        Show
        Engineered Foreign Genes
        Marker Marker Type Name
        EGFPEFGEGFP
        1 - 1 of 1
        Show
        Mapping
        No data available
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        Citation
        Santos-Ledo, A., Washer, S., Dhanaseelan, T., Eley, L., Alqatani, A., Chrystal, P.W., Papoutsi, T., Henderson, D.J., Chaudhry, B. (2020) Alternative splicing of jnk1a in zebrafish determines first heart field ventricular cardiomyocyte numbers through modulation of hand2 expression. PLoS Genetics. 16:e1008782.