Article
 

Activation of Sonic hedgehog signaling in neural progenitor cells promotes glioma development in the zebrafish optic pathway

Public Deposited

Downloadable Content

Download PDF
https://ir.library.oregonstate.edu/concern/articles/pr76f493t

Descriptions

Attribute NameValues
Creator
Abstract
  • Dysregulation of Sonic hedgehog (Shh) signaling has been implicated in glioma pathogenesis. Yet, the role of this pathway in gliomagenesis remains controversial because of the lack of relevant animal models. Using the cytokeratin 5 promoter, we ectopically expressed a constitutively active zebrafish Smoothened (Smoa1) in neural progenitor cells and analyzed tumorigenic capacity of activated Shh signaling in both transient and stable transgenic fish. Transient transgenic fish overexpressing Smoa1 developed retinal and brain tumors, suggesting smoa1 is oncogenic in the zebrafish central nervous system (CNS). We further established stable transgenic lines that simultaneously developed optic pathway glioma (OPG) and various retinal tumors. In one of these lines, up to 80% of F1 and F2 fish developed tumors within 1 year of age. Microarray analysis of tumor samples showed upregulated expression of genes involved in the cell cycle, cancer signaling and Shh downstream targets ptc1, gli1 and gli2a. Tumors also exhibited specific gene signatures characteristic of radial glia and progenitor cells as transcriptions of radial glia genes cyp19a1b, s100β, blbp, gfap and the stem/progenitor genes nestin and sox2 were significantly upregulated. Overexpression of GFAP, S100β, BLBP and Sox2 was confirmed by immunofluorescence. We also detected overexpression of Mdm2 throughout the optic pathway in fish with OPG, therefore implicating the Mdm2–Tp53 pathway in glioma pathogenesis. In conclusion, we demonstrate that activated Shh signaling initiates tumorigenesis in the zebrafish CNS and provide the first OPG model not associated with neurofibromatosis 1.
  • This is the publisher’s final pdf. The published article is copyrighted by the author(s) and published by the Nature Publishing Group. The published article can be found at: http://www.nature.com/oncsis/index.html.
  • Keywords: Sonic hedgehog (Shh) pathway, Optic pathway glioma (OPG), Zebrafish, Activated Smoothened (Smoa1)
  • Keywords: Sonic hedgehog (Shh) pathway, Optic pathway glioma (OPG), Zebrafish, Activated Smoothened (Smoa1)
Resource Type
DOI
Date Available
Date Issued
Citation
  • Ju, B., Chen, W., Spitsbergen, J. M., Lu, J., Vogel, P., Peters, J. L., ... & Taylor, M. R. (2014). Activation of Sonic hedgehog signaling in neural progenitor cells promotes glioma development in the zebrafish optic pathway. Oncogenesis, 3, e96. doi:10.1038/oncsis.2014.10
Journal Title
Journal Volume
  • 3
Rights Statement
Funding Statement (additional comments about funding)
  • This research was supported by The Hartwell Foundation, St Jude Children’s Research Hospital (SJCRH) and ALSAC. The SJCRH Cell & Tissue Imaging Center is supported by National Institutes of Health Grant NCI P30 CA021765-34.
Publisher
Peer Reviewed
Language
Replaces

Relationships

Parents:

This work has no parents.

Items

Thumbnail Title Date Uploaded Visibility Actions
file details SpitsbergenJanMicrobiologyActivationSonicHedgehog.pdf 07/26/2017 Public
file details SpitsbergenJanMicrobiologyActivationSonicHedgehog_SupplementaryMaterials.zip 07/26/2017 Public