Phenotypic chemical screening using a zebrafish neural crest EMT reporter identifies retinoic acid as an inhibitor of epithelial morphogenesis
| العنوان: | Phenotypic chemical screening using a zebrafish neural crest EMT reporter identifies retinoic acid as an inhibitor of epithelial morphogenesis |
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| المؤلفون: | Katherine K. Soh, Clifford J. Whatcott, David J. Bearss, Jindong Wang, Monique A. Morrison, Laura Jimenez, Cicely A. Jette, Steven L. Warner, Rodney A. Stewart |
| المصدر: | Disease Models & Mechanisms Disease Models & Mechanisms, Vol 9, Iss 4, Pp 389-400 (2016) |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | 0301 basic medicine, Embryo, Nonmammalian, Transcription, Genetic, Cellular differentiation, Retinoic acid, Medicine (miscellaneous), lcsh:Medicine, Animals, Genetically Modified, chemistry.chemical_compound, Neural crest, Immunology and Microbiology (miscellaneous), Cell Movement, Genes, Reporter, Drug screen, Morphogenesis, Zebrafish, Genetics, education.field_of_study, Sulfonamides, biology, EMT, Cell Differentiation, 3. Good health, Cell biology, medicine.anatomical_structure, Phenotype, embryonic structures, Reprogramming, Neural plate, lcsh:RB1-214, Signal Transduction, Research Article, Neural Tube, Epithelial-Mesenchymal Transition, Population, Green Fluorescent Proteins, Neuroscience (miscellaneous), Tretinoin, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, medicine, lcsh:Pathology, Animals, Epithelial mesenchymal, Epithelial–mesenchymal transition, education, Molecular Biology, Cell Shape, lcsh:R, Neural tube, Epithelial Cells, Zebrafish Proteins, biology.organism_classification, Zebra, Molecular biology, 030104 developmental biology, Pyrimidines, chemistry, Cancer cell, Developmental Biology |
| الوصف: | 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, whereas a later population delaminates from within the dorsal neural tube. Treating Tg(snai1b:GFP) embryos with candidate small-molecule EMT-inhibiting compounds identified TP-0903, a multi-kinase inhibitor that blocked cranial NC cell delamination in both the lateral and medial populations. RNA sequencing (RNA-Seq) analysis and chemical rescue experiments show that 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 contributes to its prior success in eliminating disseminated cancer cells. Editors' choice: Generation and characterization of a novel neural crest EMT reporter for rapid in vivo drug screening in zebrafish that identifies a small-molecule EMT inhibitor that blocks this process by activating retinoic acid signaling. |
| تدمد: | 1754-8411 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::61facfb11f73eadbf825649131d78c33 https://pubmed.ncbi.nlm.nih.gov/26794130 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....61facfb11f73eadbf825649131d78c33 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17548411 |
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