title: Developmental defects in zebrafish for classification of EGF pathway inhibitors.
abstract: 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.
authors.affiliation: Laboratory for Organogenesis and Regeneration, Université de Liège, GIGA-R B34, Sart Tilman, 4000 Liège, Belgium.
authors.forename: Benoist
authors.initials: B
authors.lastname: Pruvot
authors.affiliation: Laboratory for Organogenesis and Regeneration, Université de Liège, GIGA-R B34, Sart Tilman, 4000 Liège, Belgium.
authors.forename: Yoann
authors.initials: Y
authors.lastname: Curé
authors.affiliation: Laboratory for Organogenesis and Regeneration, Université de Liège, GIGA-R B34, Sart Tilman, 4000 Liège, Belgium.
authors.forename: Joachim
authors.initials: J
authors.lastname: Djiotsa
authors.affiliation: Laboratory for Organogenesis and Regeneration, Université de Liège, GIGA-R B34, Sart Tilman, 4000 Liège, Belgium.
authors.forename: Audrey
authors.initials: A
authors.lastname: Voncken
authors.affiliation: Laboratory for Organogenesis and Regeneration, Université de Liège, GIGA-R B34, Sart Tilman, 4000 Liège, Belgium. Electronic address: m.muller@ulg.ac.be.
authors.forename: Marc
authors.initials: M
authors.lastname: Muller
mesh_terms: D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D002357:Cartilage Diseases / Q000235:genetics; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000633:toxicity; D012769:Shock / Q000235:genetics; D015398:Signal Transduction; D020032:Tyrphostins / Q000633:toxicity; D015027:Zebrafish / Q000235:genetics* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D020032:Tyrphostins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors
keywords: Cartilage; Drug testing; Epidermal growth factor; Myelin; Vascular; Zebrafish