Institute of Biomedicine, University of Turku, FIN-20520 Turku, Finland.
Medicity Research Laboratory, University of Turku, FIN-20520 Turku, Finland.
Mol Biol Cell. 2019 Jan 15;30(2):209-218. doi: 10.1091/mbc.E18-07-0460. Epub 2018 Nov 21.
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, and reduced expression of muscle-specific genes, as well as reduced motoneuron length. The phenotypes in the skeletal muscle, as well as the defect in 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.
酪氨酸激酶抑制剂在临床上被广泛应用，但关于它们在发育中的生物体中的毒性的信息有限。在这里，我们测试了针对 ErbB 受体的酪氨酸激酶抑制剂对斑马鱼（Danio rerio）胚胎发育的影响。用广谱 pan-ErbB 抑制剂或 erbb4a 靶向反义寡核苷酸处理的胚胎表现出运动能力降低、骨骼肌纤维直径减小、肌肉特异性基因表达减少以及运动神经元长度减少。骨骼肌中的表型以及运动缺陷均可通过微注射人 ERBB4 mRNA 和转座子介导的肌肉特异性 ERBB4 过表达来挽救。通过 CRISPR/Cas9 对斑马鱼基因组中内源性 erbb4a 基因座进行靶向突变进一步控制了 ErbB4 在调节运动中的作用。这些观察结果表明，ErbB 酪氨酸激酶抑制剂可能通过涉及抑制 ErbB4 功能的机制在发育中的生物体中引起神经肌肉毒性。
