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Charles Eberhart, Tarran Pierfelice, Louis Dang, Karisa Schrek, Laura Asnaghi, Nicholas Gaiano; Notch3 Promotes Invasive Glioma Formation in the Optic Nerve and Retina but not the Brain. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1192.
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© ARVO (1962-2015); The Authors (2016-present)
Aberrant activation of Notch signaling has been widely implicated in developmental abnormalities, as well as tumor initiation in the breast and lymphoid cells. However most prior studies have focused on the Notch1 receptor, and less is known about Notch2 and Notch3. The goal of this study was to investigate the potentially distinct effects of activating these three receptors in the developing brain and eye.
Under ultrasound guidance, we infected embryonic day 9.5 and 10.5 mouse forebrain ventricles with a replication incompetent retrovirus expressing the constitutively active intracellular domain of Notch1, Notch2 or Notch3 and an alkaline phosphatase reporter.
The majority of eyes (n = 94) from animals injected with active Notch3 developed proliferative lesions arising from pigmented ocular choroid cells, retinal and optic nerve glia, or lens epithelium. Notch3-induced lesions in the choroid, retina, and optic nerve were capable of invading adjacent tissues, suggesting that they were malignant tumors. The choroidal tumors did not arise from RPE, and have some features of uveal melanoma. The glial tumors in retina and optic nerve were immunopositive for GFAP and Nestin and appeared astrocytic. While Notch3 activation induced choroidal tumors in up to 67% of eyes, Notch1 or Notch2 activation never resulted in such tumors. Active forms of Notch1 and Notch2 did generate a few small proliferative glial nodules in the retina and optic nerve, while Notch3 was ten-fold more efficient at generating growths, many of which were large invasive gliomas. All three active Notch receptors disrupted retinal patterning and caused proliferative subcapsular cataracts. Expression of active Notch1/Notch3 chimeric receptors implicated the RAM (RBPjk-association molecule) and transactivation domains (TAD) of Notch3 in generating choroidal and glial tumors, respectively. In contrast to our findings in the optic nerve and retina, introduction of active Notch receptors, including Notch3, into the brain never caused glial tumors.
Our results highlight the differential ability of Notch receptor paralogs to initiate malignant tumor formation, and suggest that glial precursors of the optic nerve and retina, but not the brain, are susceptible to transformation by Notch3.
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