ZFIN ID: ZDB-PUB-160123-9
Phenotypic chemical screening using zebrafish neural crest reporters identifies retinoid acid as an inhibitor of epithelial morphogenesis
Jimenez, L., Wang, J., Morrison, M.A., Whatcott, C., Soh, K.K., Warner, S., Bearss, D., Jette, C.A., Stewart, R.A.
Date: 2016
Source: Disease models & mechanisms   9(4): 389-400 (Journal)
Registered Authors: Jette, Cicely A., Jimenez, Laura, Morrison, Monique, Stewart, Rodney A.
Keywords: Drug screen, EMT, Epithelial mesenchymal, Neural crest, Retinoic acid, Zebrafish
Microarrays: GEO:GSE72322
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Cell Differentiation/drug effects
  • Cell Movement/drug effects
  • Cell Shape/drug effects
  • Embryo, Nonmammalian/drug effects
  • Embryo, Nonmammalian/metabolism
  • Epithelial Cells/cytology*
  • Epithelial Cells/drug effects
  • Epithelial Cells/metabolism
  • Epithelial-Mesenchymal Transition/drug effects*
  • Genes, Reporter*
  • Green Fluorescent Proteins/metabolism
  • Morphogenesis/drug effects*
  • Neural Crest/drug effects
  • Neural Crest/metabolism*
  • Neural Tube/cytology
  • Neural Tube/drug effects
  • Phenotype
  • Pyrimidines/pharmacology
  • Signal Transduction/drug effects
  • Sulfonamides/pharmacology
  • Transcription, Genetic/drug effects
  • Tretinoin/pharmacology*
  • Zebrafish/embryology
  • Zebrafish/metabolism*
  • Zebrafish Proteins/metabolism
PubMed: 26794130 Full text @ Dis. Model. Mech.
The epithelial to mesenchymal transition (EMT) is a highly conserved morphogenetic program essential for embryogenesis, regeneration and cancer metastasis. In cancer cells, EMT also triggers cellular reprogramming and chemoresistance, which underlie disease relapse and decreased survival. Hence, identifying compounds that block EMT is essential to prevent or eradicate disseminated tumor cells. Here, we establish a whole animal-based EMT reporter in zebrafish for rapid drug screening called Tg(snai1b:GFP), which labels epithelial cells undergoing EMT to produce sox10-positive neural crest (NC) cells. Time-lapse and lineage analysis of Tg(snai1b:GFP) embryos reveal that cranial NC cells delaminate from two regions; an early population delaminates adjacent to the neural plate while a later population delaminates from within the dorsal neural tube. Treating Tg(snai1b:GFP) embryos with candidate small molecule EMT compounds identified TP-0903, a multi-kinase inhibitor that blocked cranial NC delamination in both the lateral and medial populations. RNA-Seq analysis and chemical rescue experiments show TP-0903 acts through stimulating retinoic acid (RA) biosynthesis and RA-dependent transcription. These studies identify TP-0903 as a new therapeutic for activating RA in vivo and raise the possibility that RA-dependent inhibition of EMT may contribute to its prior success in eliminating disseminated cancer cells.