title: Molecular and cellular characterization of a zebrafish optic pathway tumor line implicates glia-derived progenitors in tumorigenesis.
abstract: In this study we describe the molecular and cellular characterization of a zebrafish mutant that develops tumors in the optic pathway. Heterozygous Tg(flk1:RFP)is18 transgenic adults develop tumors of the retina, optic nerve and optic tract. Molecular and genetic mapping demonstrate the tumor phenotype is linked to a high copy number transgene array integrated in the lincRNA gene lincRNAis18/Zv9_00007276 on chromosome 3. TALENs were used to isolate a 147 kb deletion allele that removes exons 2-5 of the lincRNAis18 gene. Deletion allele homozygotes are viable and do not develop tumors, indicating loss of function of the lincRNAis18 locus is not the trigger for tumor onset. Optic pathway tumors in the Tg(flk1:RFP)is18 mutant occur with a penetrance of 80-100% by 1 year of age. The retinal tumors are highly vascularized and composed of rosettes of various sizes embedded in a fibrous matrix. Immunohistochemical analysis showed increased expression of the glial markers GFAP and BLBP throughout retinal tumors and in dysplastic optic nerve. We performed transcriptome analysis of pre-tumorous retina and retinal tumor tissue and found changes in gene expression signatures of radial glia and astrocytes (slc1a3), activated glia (atf3, blbp, apoeb), proliferating neural progenitors (foxd3, nestin, cdh2, her9/hes1), and glioma markers (S100β, vim). The transcriptome also revealed activation of cAMP, Stat3 and Wnt signal transduction pathways. qRT-PCR confirmed >10-fold overexpression of the Wnt pathway components hbegfa, ascl1a, and insm1a. Together the data indicate Müller glia and/or astrocyte-derived progenitors could contribute to the zebrafish Tg(flk1:RFP)is18 optic pathway tumors.
authors.affiliation: Department of Genetics, Development and Cell Biology, Iowa State University, Ames, Iowa, United States of America.
authors.forename: Staci L
authors.initials: SL
authors.lastname: Solin
authors.affiliation: Department of Genetics, Development and Cell Biology, Iowa State University, Ames, Iowa, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Genetics, Development and Cell Biology, Iowa State University, Ames, Iowa, United States of America.
authors.forename: Joshua
authors.initials: J
authors.lastname: Mauldin
authors.affiliation: Department of Genetics, Development and Cell Biology, Iowa State University, Ames, Iowa, United States of America.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Schultz
authors.affiliation: Department of Genetics, Development and Cell Biology, Iowa State University, Ames, Iowa, United States of America.
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Lincow
authors.affiliation: Department of Genetics, Development and Cell Biology, Iowa State University, Ames, Iowa, United States of America.
authors.forename: Pavel A
authors.initials: PA
authors.lastname: Brodskiy
authors.affiliation: Department of Genetics, Development and Cell Biology, Iowa State University, Ames, Iowa, United States of America.
authors.forename: Crystal A
authors.initials: CA
authors.lastname: Jones
authors.affiliation: Department of Genetics, Development and Cell Biology, Iowa State University, Ames, Iowa, United States of America.
authors.forename: Judith
authors.initials: J
authors.lastname: Syrkin-Nikolau
authors.affiliation: Department of Genetics, Development and Cell Biology, Iowa State University, Ames, Iowa, United States of America.
authors.forename: Jasmine M
authors.initials: JM
authors.lastname: Linn
authors.affiliation: Department of Genetics, Development and Cell Biology, Iowa State University, Ames, Iowa, United States of America.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Essner
authors.affiliation: Department of Veterinary Pathology, Iowa State University, Ames, Iowa, United States of America.
authors.forename: Jesse M
authors.initials: JM
authors.lastname: Hostetter
authors.affiliation: Department of Veterinary Pathology, Iowa State University, Ames, Iowa, United States of America.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Whitley
authors.affiliation: Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: J Douglas
authors.initials: JD
authors.lastname: Cameron
authors.affiliation: Department of Genetics, Development and Cell Biology, Iowa State University, Ames, Iowa, United States of America.
authors.forename: Hui-Hsien
authors.initials: HH
authors.lastname: Chou
authors.affiliation: Genome Informatics Facility, Office of Biotechnology, Iowa State University, Ames, Iowa, United States of America.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Severin
authors.affiliation: Department of Genetics, Development and Cell Biology, Iowa State University, Ames, Iowa, United States of America.
authors.forename: Donald S
authors.initials: DS
authors.lastname: Sakaguchi
authors.affiliation: Department of Genetics, Development and Cell Biology, Iowa State University, Ames, Iowa, United States of America.
authors.forename: Maura
authors.initials: M
authors.lastname: McGrail
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified / Q000254:growth & development*; D015139:Blotting, Southern; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D007124:Immunoenzyme Techniques; D009457:Neuroglia / Q000166:cytology* / Q000378:metabolism; D009900:Optic Nerve / Q000166:cytology* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D014795:Visual Pathways / Q000166:cytology* / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D029961:Zebrafish Proteins