Purchase this article with an account.
Maura McGrail, Pavel A. Brodskiy, Elizabeth M. Whitley, Donald S. Sakaguchi, Jeffrey J. Essner; A Genetic Model of Retinoblastoma in Zebrafish. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1371.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Cancer mortality rates in the US remain high due in part to insufficient treatments for invasive and metastatic disease. Animal models of human cancers are important for defining new genetic pathways in order to reveal novel therapeutic targets. We have isolated a zebrafish mutation that results in retinal tumors and behaves genetically like human retinoblastoma, with inheritance of one mutant locus preceding disease onset. The purpose of this study is to establish the genetic, pathological and histological similarities between the zebrafish retinal tumor model and human inherited retinoblastoma.
We isolated a transgenic zebrafish line, Tg(flk1a:tagrfp-caax)is8, that expresses a membrane tethered red fluorescent protein in the vascular system. At 1.5 years of age 7/8 transgenic F1 fish had developed unilateral or bi-lateral eye tumors. Tumor positive F1 fish were outcrossed to test whether the tumor phenotype was linked to inheritance of the transgene. Adult F1 fish were sacrificed and heads processed for histopathology and immunohistochemistry with antibodies to neuronal, photoreceptor, and glial markers.
In the F2 generation eye tumors appeared in 8/21 of progeny that had inherited the Tg(flk1a:tagrfp-caax)is8 transgene. Eye tumors did not develop in 22 control siblings. Analyses of the eye tumors revealed over-proliferation of neural cell layers, disorganized synaptic layers, formation of Homer-Wright rosettes containing primitive photoreceptor cells arranged around a central lumen, and invasion through the wall of the eye. Addi-tionally, affected fish had morphologic changes in the optic nerve and in the brain.
The analyses demonstrate the zebrafish eye tumors originate in the neural retina and show key pathologic features consistent with human retinoblastoma. Tumor onset appears linked to the Tg(flk1a:tagrfp-caax)is8 transgene insertion site. Identification of the potential tumor suppressor gene at the insertion site will reveal important information about the genetic basis of the zebrafish retinal tumors. Our zebrafish retinal tumor model provides a novel genetic system for investigating the genetics of retinoblastoma onset and progression.
This PDF is available to Subscribers Only