TY - JOUR
T1 - Molecular and cellular characterization of α zebrafish optic pathway tumor line implicates glia-derived progenitors in tumorigenesis
AU - Solin, Staci L.
AU - Wang, Ying
AU - Mauldin, Joshua
AU - Schultz, Laura E.
AU - Lincow, Deborah E.
AU - Brodskiy, Pavel A.
AU - Jones, Crystal A.
AU - Syrkin-Nikolau, Judith
AU - Linn, Jasmine M.
AU - Essner, Jeffrey J.
AU - Hostetter, Jesse M.
AU - Whitley, Elizabeth M.
AU - Cameron, J. Douglas
AU - Chou, Hui Hsien
AU - Severin, Andrew J.
AU - Sakaguchi, Donald S.
AU - McGrail, Maura
N1 - Publisher Copyright:
© 2014 Solin et al.
PY - 2014/12/8
Y1 - 2014/12/8
N2 - 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 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.
AB - 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 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.
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U2 - 10.1371/journal.pone.0114888
DO - 10.1371/journal.pone.0114888
M3 - Article
AN - SCOPUS:84915825901
SN - 1932-6203
VL - 9
JO - PloS one
JF - PloS one
IS - 12
M1 - e114888
ER -
