title: Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration.
abstract: Cone phototransduction and survival of cones in the human macula is essential for color vision and for visual acuity. Progressive cone degeneration in age-related macular degeneration, Stargardt disease, and recessive cone dystrophies is a major cause of blindness. Thyroid hormone (TH) signaling, which regulates cell proliferation, differentiation, and apoptosis, plays a central role in cone opsin expression and patterning in the retina. Here, we investigated whether TH signaling affects cone viability in inherited retinal degeneration mouse models. Retinol isomerase RPE65-deficient mice [a model of Leber congenital amaurosis (LCA) with rapid cone loss] and cone photoreceptor function loss type 1 mice (severe recessive achromatopsia) were used to determine whether suppressing TH signaling with antithyroid treatment reduces cone death. Further, cone cyclic nucleotide-gated channel B subunit-deficient mice (moderate achromatopsia) and guanylate cyclase 2e-deficient mice (LCA with slower cone loss) were used to determine whether triiodothyronine (T3) treatment (stimulating TH signaling) causes deterioration of cones. We found that cone density in retinol isomerase RPE65-deficient and cone photoreceptor function loss type 1 mice increased about sixfold following antithyroid treatment. Cone density in cone cyclic nucleotide-gated channel B subunit-deficient and guanylate cyclase 2e-deficient mice decreased about 40% following T3 treatment. The effect of TH signaling on cone viability appears to be independent of its regulation on cone opsin expression. This work demonstrates that suppressing TH signaling in retina dystrophy mouse models is protective of cones, providing insights into cone preservation and therapeutic interventions.
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Ma
authors.forename: Arjun
authors.initials: A
authors.lastname: Thapa
authors.forename: Lynsie
authors.initials: L
authors.lastname: Morris
authors.forename: T Michael
authors.initials: TM
authors.lastname: Redmond
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baehr
authors.forename: Xi-Qin
authors.initials: XQ
authors.lastname: Ding
mesh_terms: D000818:Animals; D013956:Antithyroid Agents / Q000494:pharmacology; D003117:Color Vision Defects / Q000150:complications* / Q000188:drug therapy; D055358:Cone Opsins / Q000378:metabolism; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000172:deficiency; D006162:Guanylate Cyclase / Q000172:deficiency; D057130:Leber Congenital Amaurosis / Q000150:complications* / Q000188:drug therapy; D008713:Methimazole; D051379:Mice; D018345:Mice, Knockout; D011956:Receptors, Cell Surface / Q000172:deficiency; D017949:Retinal Cone Photoreceptor Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D012162:Retinal Degeneration / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000502:physiology*; D013963:Thyroid Hormones / Q000378:metabolism*; D014284:Triiodothyronine / Q000494:pharmacology; D019745:cis-trans-Isomerases / Q000172:deficiency; D000099178:Retinoid Isomerohydrolase
chemical_list: D013956:Antithyroid Agents; D055358:Cone Opsins; D054815:Cyclic Nucleotide-Gated Cation Channels; D006162:Guanylate Cyclase; D008713:Methimazole; D011956:Receptors, Cell Surface; D013963:Thyroid Hormones; D014284:Triiodothyronine; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase; C532622:CNGB3 protein, mouse; C484780:Gucy2e protein, mouse