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

Lookup NU author(s): Dr Adrian Santos, Sam Washer, Dr Tamilvendhan Dhanaseelan, Dr Lorraine Eley, Paul Chrystal, Tania Papoutsi, Professor Deborah Henderson, Dr Bill Chaudhry

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.


Publication metadata

Author(s): Santos-Ledo A, Washer S, Dhanaseelan T, Eley L, Alqatani A, Chrystal PW, Papoutsi T, Henderson DJ, Chaudhry B

Publication type: Article

Publication status: Published

Journal: PLoS Genetics

Year: 2020

Volume: 16

Issue: 5

Online publication date: 18/05/2020

Acceptance date: 18/04/2020

Date deposited: 16/06/2020

ISSN (print): 1553-7390

ISSN (electronic): 1553-7404

Publisher: Public Library of Science

URL: https://doi.org/10.1371/journal.pgen.1008782

DOI: 10.1371/journal.pgen.1008782

PubMed id: 32421721


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