title: Mosaic zebrafish transgenesis for functional genomic analysis of candidate cooperative genes in tumor pathogenesis.
abstract: Comprehensive genomic analysis has uncovered surprisingly large numbers of genetic alterations in various types of cancers. To robustly and efficiently identify oncogenic "drivers" among these tumors and define their complex relationships with concurrent genetic alterations during tumor pathogenesis remains a daunting task. Recently, zebrafish have emerged as an important animal model for studying human diseases, largely because of their ease of maintenance, high fecundity, obvious advantages for in vivo imaging, high conservation of oncogenes and their molecular pathways, susceptibility to tumorigenesis and, most importantly, the availability of transgenic techniques suitable for use in the fish. Transgenic zebrafish models of cancer have been widely used to dissect oncogenic pathways in diverse tumor types. However, developing a stable transgenic fish model is both tedious and time-consuming, and it is even more difficult and more time-consuming to dissect the cooperation of multiple genes in disease pathogenesis using this approach, which requires the generation of multiple transgenic lines with overexpression of the individual genes of interest followed by complicated breeding of these stable transgenic lines. Hence, use of a mosaic transient transgenic approach in zebrafish offers unique advantages for functional genomic analysis in vivo. Briefly, candidate transgenes can be coinjected into one-cell-stage wild-type or transgenic zebrafish embryos and allowed to integrate together into each somatic cell in a mosaic pattern that leads to mixed genotypes in the same primarily injected animal. This permits one to investigate in a faster and less expensive manner whether and how the candidate genes can collaborate with each other to drive tumorigenesis. By transient overexpression of activated ALK in the transgenic fish overexpressing MYCN, we demonstrate here the cooperation of these two oncogenes in the pathogenesis of a pediatric cancer, neuroblastoma that has resisted most forms of contemporary treatment.
authors: Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic College of Medicine, Center for Individualized Medicine.
authors: Choong Yong
authors: CY
authors: Ung
authors: Tufts University School of Medicine.
authors: Feng
authors: F
authors: Guo
authors: Department of Biochemistry and Molecular Biology, Mayo Clinic.
authors: Xiaoling
authors: X
authors: Zhang
authors: Department of Biochemistry and Molecular Biology, Mayo Clinic.
authors: Zhihui
authors: Z
authors: Zhu
authors: Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic College of Medicine, Center for Individualized Medicine; Department of Biochemistry and Molecular Biology, Mayo Clinic; Zhu.Shizhen@mayo.edu.
authors: Shizhen
authors: S
authors: Zhu
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D030801:Animals, Genetically Modified; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D006801:Humans; D008164:Luminescent Proteins / Q000096:biosynthesis / Q000235:genetics; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism; D009857:Oncogenes; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D019076:Transgenes; D015027:Zebrafish / Q000235:genetics*; D000097573:Red Fluorescent Protein
chemical_list: D000077548:Anaplastic Lymphoma Kinase; D008164:Luminescent Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000097573:Red Fluorescent Protein; C000626173:ALK protein, human