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Molecular and Cellular Characterization of a Zebrafish Optic Pathway Tumor Line Implicates Glia-Derived Progenitors in Tumorigenesis
PLoS One
  • Staci L. Solin, Iowa State University
  • Ying Wang, Iowa State University
  • Joshua Mauldin, Iowa State University
  • Laura E. Schultz, Iowa State University
  • Deborah E. Lincow, Iowa State University
  • Pavel A. Brodskiy, Iowa State University
  • Crystal A. Jones, Iowa State University
  • Judith Syrkin-Nikolau, Iowa State University
  • Jasmine M. Linn, Iowa State University
  • Jeffrey J. Essner, Iowa State University
  • Jesse M. Hostetter, Iowa State University
  • Elizabeth M. Whitley, Iowa State University
  • J. Douglas Cameron, University of Minnesota - Twin Cities
  • Hui-Hsien Chou, Iowa State University
  • Andrew J. Severin, Iowa State University
  • Donald S. Sakaguchi, Iowa State University
  • Maura McGrail, Iowa State University
Document Type
Article
Publication Version
Published Version
Publication Date
1-1-2014
DOI
10. 1371/journal.pone.0114888
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 147kb 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 thelincRNAis18 locus is not the trigger for tumor onset. Optic pathway tumors in theTg(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.

Comments

This article is from PLoS One 9 (2014): e114888, doi:10.1371/journal.pone.0114888. Posted with permission.

Rights
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Copyright Owner
Staci L. Solin, et al
Language
en
File Format
application/pdf
Citation Information
Staci L. Solin, Ying Wang, Joshua Mauldin, Laura E. Schultz, et al.. "Molecular and Cellular Characterization of a Zebrafish Optic Pathway Tumor Line Implicates Glia-Derived Progenitors in Tumorigenesis" PLoS One Vol. 9 Iss. 12 (2014) p. 1 - 31
Available at: http://works.bepress.com/maura-mcgrail/3/