ErbB4 tyrosine kinase inhibition impairs neuromuscular development in zebrafish embryos

Area of Science:

• Developmental Biology
• Neuroscience
• Pharmacology

Background:

• Tyrosine kinase inhibitors (TKIs) are crucial in cancer therapy.
• Limited data exist on TKI toxicity in developing organisms.
• ErbB receptors play roles in cellular growth and differentiation.

Purpose of the Study:

• To investigate the effects of ErbB-targeting TKIs on developing zebrafish embryos.
• To elucidate the role of ErbB4 in neuromuscular development and motility.
• To assess the potential for ErbB-targeting TKIs to induce neuromuscular toxicity.

Main Methods:

• Treatment of zebrafish embryos with pan-ErbB inhibitors and erbb4a-targeting antisense oligonucleotides.
• Assessment of locomotion, skeletal muscle fiber diameter, muscle-specific gene expression, and motoneuron length.
• Rescue experiments using microinjection of human ERBB4 mRNA and transposon-mediated ERBB4 overexpression.
• CRISPR/Cas9-mediated targeted mutation of the erbb4a locus.

Main Results:

• ErbB inhibition led to reduced locomotion, smaller skeletal muscle fibers, decreased muscle gene expression, and shorter motoneurons.
• Phenotypes were rescued by restoring ErbB4 function through mRNA injection or overexpression.
• CRISPR/Cas9 confirmed ErbB4's role in regulating motility.

Conclusions:

• ErbB-targeting TKIs can induce neuromuscular toxicity in developing zebrafish.
• Inhibition of ErbB4 signaling is a key mechanism underlying this toxicity.
• Findings highlight the importance of considering developmental toxicity of TKIs.