Abstract
In the central nervous system injury induces cellular reprogramming and progenitor proliferation, but the molecular mechanisms that limit regeneration and prevent tumorigenesis are not completely understood. We previously described a zebrafish optic pathway tumor model in which transgenic Tg(flk1:RFP)is18/+ adults develop nonmalignant retinal tumors. Key pathways driving injury-induced glial reprogramming and regeneration contributed to tumor formation. In this study, we examine a time course of proliferation and present new analyses of the Tg(flk1:RFP)is18/+ dysplastic retina and tumor transcriptomes. Retinal dysplasia was first detected in 3-month-old adults, but was not limited to a specific stem cell or progenitor niche. Pathway analyses suggested a decrease in cellular respiration and increased expression of components of Hif1-α, VEGF, mTOR, NFκβ, and multiple interleukin pathways are associated with early retinal dysplasia. Hif-α targets VEGFA (vegfab) and Leptin (lepb) were both highly upregulated in dysplastic retina; however, each showed distinct expression patterns in neurons and glia, respectively. Phospho-S6 immunolabeling indicated that mTOR signaling is activated in multiple cell populations in wild-type retina and in the dysplastic retina and advanced tumor. Our results suggest that multiple pathways may contribute to the continuous proliferation of retinal progenitors and tumor growth in this optic pathway tumor model. Further investigation of these signaling pathways may yield insight into potential mechanisms to control the proliferative response during regeneration in the nervous system.
Highlights
Elucidating the molecular mechanisms controlling cellular reprogramming and regeneration is important for improved treatment of nervous system injury and disease
In this study we examined the onset of ectopic proliferation in the retina of adult Tg(flk1:RFP)is18/+ zebrafish predisposed to nonmalignant retinal tumors and analyzed activation of signaling pathways that correlate with retinal dysplasia and tumor growth
A second major finding of our study is that expression of VEGFA and Leptin is significantly increased in early dysplastic retina, before formation of large lesions or tumors
Summary
Elucidating the molecular mechanisms controlling cellular reprogramming and regeneration is important for improved treatment of nervous system injury and disease. In injured tissue dying cells and damaged vasculature lead to inflammation and a hypoxic environment.[1,2] The pro-inflammatory cytokine and hypoxia inducible factor Hif-a pathways are critical for mediating the cellular response to cell death and hypoxia.[3,4] How activation of hypoxia and inflammatory pathways contribute to proliferation and regeneration in the nervous system is still not completely understood. Hypoxia has been shown to activate regeneration gene programs in injured peripheral sensory neurons by Hif1-a induced expression of its direct target, the vascular endothelial growth factor (VEGF).[5] VEGF receptor tyrosine kinase signaling is essential to embryonic blood vessel development, adult angiogenesis, tumor vascularization, and disease-related vascular retinopathies.[6] In addition, multiple nonvascular functions have been described for VEGF in the developing and adult central nervous system (CNS).[7,8] VEGF is expressed by glial progenitors and astrocytes in response to hypoxia in the neonatal subventricular zone and stimulates a Laura E.
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