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W.T. Allison, S.G. Dann, C.W. Hawryshyn; Cone Regeneration during Natural Development: Thyroid Hormone Effects . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2819.
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Purpose: Ultraviolet-sensitive (UVS) cones disappear from the retina of salmonid fishes during the metamorphosis that prepares them for marine life. At sexual maturity, when migratory populations of fish return to freshwater, a population of putative UVS cones has been reported to reappear into the retina. Our goals were to determine: i. the identity of these reappearing cells; ii. if retinal stem cells are their source; and iii. if they are functional at the level of electroretinogram (ERG) analysis. Methods: Thyroid hormone (TH) plays a role in metamorphosis and sexual maturation and directly affects retinal cells. Thus rainbow trout (Oncorhynchus mykiss) were treated with TH, which results in the apoptosis of UVS cones. We utilized ERGs and our in situ hybridization and immunohistochemical labels to determine distributions of UVS cones several weeks after cessation of TH treatment. BrdU was applied after cessation of TH treatment and retina were examined for its presence in UVS cones. Results: Labeling of photoreceptors and ERGs support the hypothesis that TH application mimics natural development, including the loss and reappearance of UVS cones. Cessation of TH treatment results in the reappearance of UVS cones in positions (central retina) that exclude the peripheral retina as being the source. BrdU double labeling with either in situ hybridization or immunohistochemical labels (which label different areas of the UVS opsin) indicate that UVS cones regenerate from dividing stem cells. ERGs indicate that sensitivity to ultraviolet light returns in some fish, depending on time of recovery. Conclusions: The findings are the first to confirm that cones expressing UVS opsin can reappear into the retina. These observations are consistent with the hypothesis that the reappearance of UVS cones occurs through the proliferation of stem cells, which are known to reside in teleost retinae. Further, these data suggest that TH is altering the developmental trajectory of stem cells, affecting a rod vs. cone cell fate. Our previous data indicate that opsin promoters are bound by transcription factors that implicate TH in the regulation of apoptosis/proliferation. The regeneration of UVS cones occurs during natural retinal development in salmonid fishes. This allows an examination of signals and gene expression inducing regeneration of cones from proliferating stem cells. Importantly, such studies can be conducted in vivo, without confounds of retinal damage, which is normally utilized to study such events. Supported by a Fellowship from the Alzheimer Society of Canada and the CIHR Institute of Aging (WTA), fellowship & operating grants from NSERC (SGD & CWH).
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