ZFIN ID: ZDB-PUB-140102-11
Developmental defects in zebrafish for classification of EGF pathway inhibitors
Pruvot, B., Curé, Y., Djiotsa, J., Voncken, A., and Muller, M.
Date: 2014
Source: Toxicology and applied pharmacology   274(2): 339-349 (Journal)
Registered Authors: Muller, Marc
Keywords: zebrafish, epidermal growth factor, cartilage, vascular, drug testing, myelin
MeSH Terms:
  • Animals
  • Blood Flow Velocity/drug effects
  • Cartilage Diseases/genetics
  • Epidermal Growth Factor/antagonists & inhibitors*
  • Epidermal Growth Factor/genetics
  • Epidermal Growth Factor/metabolism
  • Gene Expression Regulation, Developmental/drug effects*
  • Myelin Sheath/genetics
  • Myelin Sheath/metabolism
  • Protein Kinase Inhibitors/toxicity
  • Shock/genetics
  • Signal Transduction*
  • Tyrphostins/toxicity
  • Zebrafish/genetics*
  • Zebrafish/metabolism
PubMed: 24262764 Full text @ Tox. App. Pharmacol.

One of the major challenges when testing drug candidates targeted at a specific pathway in whole animals is the discrimination between specific effects and unwanted, off-target effects. Here we used the zebrafish to define several developmental defects caused by impairment of Egf signaling, a major pathway of interest in tumor biology. We inactivated Egf signaling by genetically blocking Egf expression or using specific inhibitors of the Egf receptor function. We show that the combined occurrence of defects in cartilage formation, disturbance of blood flow in the trunk and a decrease of myelin basic protein expression represent good indicators for impairment of Egf signaling. Finally, we present a classification of known tyrosine kinase inhibitors according to their specificity for the Egf pathway.

In conclusion, we show that developmental indicators can help to discriminate between specific effects on the target pathway from off-target effects in molecularly targeted drug screening experiments in whole animal systems.