A1 Refereed original research article in a scientific journal
ErbB4 tyrosine kinase inhibition impairs neuromuscular development in zebrafish embryos
Authors: Paatero I, Veikkolainen V, Mäenpää M, Schmelzer E, Belting HG, Pelliniemi LJ, Elenius K
Publication year: 2019
Journal: Molecular Biology of the Cell
Journal name in source: Molecular biology of the cell
Journal acronym: Mol Biol Cell
Volume: 30
Issue: 2
First page : 209
Last page: 218
Number of pages: 10
ISSN: 1059-1524
eISSN: 1939-4586
DOI: https://doi.org/10.1091/mbc.E18-07-0460
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/37474472
Tyrosine kinase inhibitors are widely used in the clinic, but limited information is available about their toxicity in developing organisms. Here, we tested the effect of tyrosine kinase inhibitors targeting the ErbB receptors for their effects on developing zebrafish ( Danio rerio) embryos. Embryos treated with wide-spectrum pan-ErbB inhibitors or erbb4a-targeting antisense oligonucleotides demonstrated reduced locomotion, reduced diameter of skeletal muscle fibers, reduced expression of muscle-specific genes, as well as reduced motoneuron length. The phenotypes in the skeletal muscle, as well as the defect in the motility, were rescued both by microinjection of human ERBB4 mRNA, and by transposon-mediated muscle-specific ERBB4 overexpression. The role of ErbB4 in regulating motility was further controlled by targeted mutation of the endogenous erbb4a locus in the zebrafish genome by CRISPR/Cas9. These observations demonstrate a potential for the ErbB tyrosine kinase inhibitors to induce neuromuscular toxicity in a developing organism via a mechanism involving inhibition of ErbB4 function.
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