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Decreased, Triiodothyronine (T3) leads to Altered, Photoreceptor patterning
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Thyroperoxidase inhibition leading to altered visual function via altered photoreceptor patterning||adjacent||Lucia Vergauwen (send email)||Under development: Not open for comment. Do not cite||Under Development|
Life Stage Applicability
Key Event Relationship Description
Thyroid hormone signaling coordinates cell fate of photoreceptors in the visual system, especially during development and growth. Although different taxonomic groups differ in their photoreceptor subtypes, in general across species, thyroid hormone action promotes a shift of spectral sensitivity of opsins toward longer wavelengths. Decreased serum levels of triiodothyronine (T3), the more biologically active thyroid hormone, can alter photoreceptor patterning.
Evidence Collection Strategy
Evidence Supporting this KER
It is widely accepted that thyroid hormones play a role in the development of the visual system, and specifically in the development of the normal photoreceptor pattern in the retina. It follows that decreased availability of T3 in serum disrupts the normal photoreceptor pattern.
Uncertainties and Inconsistencies
Mackin et al. (2019): All 4 cone opsins are regulated by T4. However, in athyroid juvenile zebrafish, sws1 and sws2 levels were not different compared to controls, findings which are not consistent with endogenous functions for TH signaling in regulation of these genes in juvenile zebrafish.
Some studies show that TH can still alter opsin expression in later life stages after retinal development, while other studies report that opsin expression remains unaltered but the wavelength where maximal absorbance occurs increases.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The function of thyroid hormones in regulating eye development including photoreceptor patterning is highly conserved across vertebrates (Viets et al., 2016)
Species that undergo noticeable metamorphosis seem to have more plasticity in opsin expression both at the embryonic stage and when the retina is fully differentiated (Suliman and Flamarique, 2014).
Mackin et al. (2019): Lws and Rh2 differential Expression Remains Plastic to the Effects of TH Signaling through Juvenile Growth.
Mackin et al. (2019): components of the zebrafish rh2 opsin gene array can also be regulated by exogenous T3 in larval zebrafish.
Zebrafish are undifferentiated gonochorists since both sexes initially develop an immature ovary (Maack and Segner, 2003). Immature ovary development progresses until approximately the onset of the third week. Later, in female fish immature ovaries continue to develop further, while male fish undergo transformation of ovaries into testes. Final transformation into testes varies among male individuals, however finishes usually around 6 weeks post fertilization. Effects on photoreceptor patterning resulting from altered T3 levels during early development are therefore expected to be independent of sex.
Glaschke et al. (2011) showed that TH also controls adult cone opsin expression in mice and rats.
Mader and Cameron (2006): Premetamorphic winter flounder express only RH2 opsin. During metamorphosis they develop a new repertoire of opsins (RH1, SWS2, RH2, and LWS). the phenotypic organization of the premetamorphic retina, which is produced during low TH conditions, is consistent with the premetamorphic-like retina produced by the growing postmetamorphic retina during induced hypothyroidic conditions. Additionally, a similar effect of TH upon photoreceptor production was observed for regenerating postmetamorphic retina. This suggests that regeneration of the adult vertebrate retina involves a recapitulation of the mechanisms that drive and direct cytogenesis during normal development and growth
While in early life stages during retinal development, TH alters opsin expression and photoreceptor fate, during later stages TH treatment does not always result in altered opsin expression:
Allison et al. (2004) showed that thyroid hormone treatment increases the wavelength of maximum absorbance of photoreceptors in adult zebrafish, and this could not be explained by changes in opsin expression.
Suliman and Novales Flamarique (2014): Opsin expression did not change in young juveniles of zebrafish or killifish treated with TH.
Allison, W.T., Dann, S.G., Veldhoen, K.M., Hawryshyn, C.W., 2006. Degeneration and regeneration of ultraviolet cone photoreceptors during development in rainbow trout. Journal of Comparative Neurology 499, 702-715.
Allison, W.T., Haimberger, T.J., Hawryshyn, C.W., Temple, S.E., 2004. Visual pigment composition in zebrafish: Evidence for a rhodopsin-porphyropsin interchange system. Visual Neuroscience 21, 945-952.
Cheng, C.L., Flamarique, I.N., Harosi, F.I., Rickers-Haunerland, J., Haunerland, N.H., 2006. Photoreceptor layer of salmonid fishes: Transformation and loss of single cones in juvenile fish. Journal of Comparative Neurology 495, 213-235.
Ding XQ, Ma H. (2016) Thyroid Hormone Signaling and Cone Photoreceptor Viability. In: Bowes Rickman C., LaVail M., Anderson R., Grimm C., Hollyfield J., Ash J. (eds) Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology, vol 854. Springer, Cham. https://doi.org/10.1007/978-3-319-17121-0_81
DuVal, M.G., Allison, W.T., 2018. Photoreceptor Progenitors Depend Upon Coordination of gdf6a, thr beta, and tbx2b to Generate Precise Populations of Cone Photoreceptor Subtypes. Investigative Ophthalmology & Visual Science 59, 6089-6101.
Gamborino, M. J., Sevilla-Romero, E., Muñoz, A., Hernández-Yago, J., Renau-Piqueras, J., & Pinazo-Durán, M. D. (2001). Role of thyroid hormone in craniofacial and eye development using a rat model. Ophthalmic Research, 33(5), 283–291. https://doi.org/10.1159/000055682
Gan, K.J., Flamarique, I.N., 2010. Thyroid Hormone Accelerates Opsin Expression During Early Photoreceptor Differentiation and Induces Opsin Switching in Differentiated TR alpha-Expressing Cones of the Salmonid Retina. Developmental Dynamics 239, 2700-2713.
Glaschke, A., Glosmann, M., Peichl, L., 2010. Developmental Changes of Cone Opsin Expression but Not Retinal Morphology in the Hypothyroid Pax8 Knockout Mouse. Investigative Ophthalmology & Visual Science 51, 1719-1727.
Glaschke, A., Weiland, J., Del Turco, D., Steiner, M., Peichl, L., Glosmann, M., 2011. Thyroid Hormone Controls Cone Opsin Expression in the Retina of Adult Rodents. Journal of Neuroscience 31, 4844-4851.
Houbrechts, A.M., Vergauwen, L., Bagci, E., Van Houcke, J., Heijlen, M., Kulemeka, B., Hyde, D.R., Knapen, D., Darras, V.M., 2016. Deiodinase knockdown affects zebrafish eye development at the level of gene expression, morphology and function. Molecular and Cellular Endocrinology 424, 81-93.
Maack, G., Segner, H., 2003. Morphological development of the gonads in zebrafish. Journal of Fish Biology 62, 895-906.
Mackin, R.D., Frey, R.A., Gutierrez, C., Farre, A.A., Kawamura, S., Mitchell, D.M., Stenkamp, D.L., 2019. Endocrine regulation of multichromatic color vision. Proceedings of the National Academy of Sciences of the United States of America 116, 16882-16891.
Mader, M., Cameron, D., 2006. Effects of induced systemic hypothyroidism upon the retina: Regulation of thyroid hormone receptor alpha and photoreceptor production. Molecular Vision 12, 915-930.
Ng, L., Hurley, L.B., Dierks, B., Srinivas, M., Salto, C., Vennstrom, B., Reh, T.A., Forrest, D., 2001. A thyroid hormone receptor that is required for the development of green cone photoreceptors. Nature Genetics 27, 94-98.
Ng, L., Lu, A., Swaroop, A., Sharlin, D.S., Swaroop, A., Forrest, D., 2011. Two transcription factors can direct three photoreceptor outcomes from rod precursor cells in mouse retinal development. J Neurosci 31, 11118-11125.
Roberts, M.R., Srinivas, M., Forrest, D., Morreale de Escobar, G., Reh, T.A., 2006. Making the gradient: thyroid hormone regulates cone opsin expression in the developing mouse retina. Proc Natl Acad Sci U S A 103, 6218-6223.
Suliman, T., Flamarique, I.N., 2014. Visual Pigments and Opsin Expression in the Juveniles of Three Species of Fish (Rainbow Trout, Zebrafish, and Killifish) Following Prolonged Exposure to Thyroid Hormone or Retinoic Acid. Journal of Comparative Neurology 522, 98-117.
Suzuki, S.C., Bleckert, A., Williams, P.R., Takechi, M., Kawamura, S., Wong, R.O.L., 2013. Cone photoreceptor types in zebrafish are generated by symmetric terminal divisions of dedicated precursors. Proceedings of the National Academy of Sciences of the United States of America 110, 15109-15114.
Vancamp, P., Houbrechts, A.M., Darras, V.M., 2019. Insights from zebrafish deficiency models to understand the impact of local thyroid hormone regulator action on early development. General and Comparative Endocrinology 279, 45-52.
Viets, K., Eldred, K.C., Johnston, R.J., 2016. Mechanisms of Photoreceptor Patterning in Vertebrates and Invertebrates. Trends in Genetics 32, 638-659.