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Relationship: 2378

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Decreased, Triiodothyronine (T3) leads to Altered, Photoreceptor patterning

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Decreased, Triiodothyronine (T3)

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Altered, Photoreceptor patterning

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

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			Cataia Ives (send email)	Under development: Not open for comment. Do not cite	Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
zebrafish	Danio rerio		NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

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

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

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.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

There is ample evidence across species that thyroid hormones (TH) promote a switch/shift to photoreceptors with opsins sensitive to longer wavelengths:

Thyroid hormone action is known to be required for M-opsin identity in mice (and rats)
- Using thrb2 knockout mice, Ng et al. (2001) showed that TH reduces S (short wavelength opsin) cones and promotes M (medium wavelength opsin) cones.
- Roberts et al. (2006) also showed that exogenous TH inhibits S-opsin expression, but activates M-opsin expression via thrbeta2 action. Furthermore, they found a spatial TH gradient with more TH in the dorsal retina, that corresponded to the spatial pattern of more M-opsin in the dorsal retina, confirming that THs determine spatial patterning of photoreceptors.
- Ng et al. (2011) concluded that in mice photoreceptor diversity originates in a common precursor with default S cone properties and differentiation is a two-step process where neural retina leucine zipper factor (NRL) first promotes differentiation of a fraction of precursor cells to rods and thrbeta2 secondly promotes differentiation of another fraction to M cones.
- Glaschke et al. (2010) showed that a postnatal decrease in serum thyroid hormone resulted in upregulation of S opsin was upregulated in all cones, whereas M opsin was downregulated throughout the retina.
- Glaschke et al. (2011) showed that TH also controls adult cone opsin expression. Methimazole-induced suppression of serum TH in adult mice and rats yielded no changes in cone numbers but reversibly altered cone patterns by activating the expression of S-cone opsin and repressing the expression of M-cone opsin. Treatment of athyroid mice with TH restored a wild-type pattern of cone opsin expression that reverted back to the mutant S-opsin-dominated pattern after termination of treatment. No evidence for cone death or the generation of new cones from retinal progenitors was found in retinas that shifted opsin expression patterns.
- Gamborino et al. () found a delay in photoreceptor outer segment morphogenesis (in relation to retarded disc formation) and significantly lower values for ganglion cell nuclear volumes (p > 0.001) and nuclear pore density (p > 0.01) in the TH deficient rats
- Ma Ding (2016) found out that treatment with thyroid hormone triiodothyronine (T3) or induction of high T3 by deleting the hormone-inactivating enzyme type 3 iodothyronine deiodinase (DIO3) causes cone death in mice.
Salmonids undergo indirect development with an intermediate metamorphosis. In salmonids, this includes a switch from UV cones to blue cones (Cheng et al., 2006). Thyroid hormone action is known to be required for this opsin switch:
- Allison et al. (2006) showed that increasing thyroid hormone (TH) levels led to UVS cone degeneration in rainbow trout, which is part of metamorphosis that prepares them for deeper/marine waters. After the cessation of TH treatment, UVS cones regenerated in the retina. Labeling demonstrated that UVS cone degeneration occurs via programmed cell death.
- Cheng et al. (2006): Thyroid hormone induced a reversible UV-to-blue opsin switch in differentiated single cones of juvenile salmonids (alevin and parr stages), but did not have a similar effect on the retina of older fish (smolt stage).
- Gan and Flamarique (2010) showed that thyroid hormone accelerated opsin expression in differentiating cones and induced the opsin switch (from UV sensitive cones to blue cones sensitive to longer wavelengths) in differentiated single cones, whereas propylthiouracil (PTU) repressed the opsin switch in the salmonid retina. TRalpha spatial expression patterns paralleled the progression of the opsin switch.
- Suliman and Novales Flamarique (2014): In both alevins and smolt (large juvenile rainbow trout) of rainbow trout, thyroid hormone treatment significantly increased the wavelength of maximum absorbance of the M and L visual pigments. While in alevins this was accompanied by a switch of S-opsin expression from UV to blue opsin, opsin expression in smolt remained unchanged.
- Duval and Allison (2018): TH promotes red cones and restricts UV cones via thrb during early development of zebrafish. During later development it additionally restricts blue cones.
Thyroid hormone action is known to be required for long-wavelength-sensitive cone identity in zebrafish.
- Suzuki et al. (2013): Thyroid hormone receptor β2 expression in cone precursors is required to produce pure red cones.
- Houbrechts et al. (2016): Knockdown of deiodinase 1 and 2 in zebrafish embryos (expected to result in decreased levels of T3) decreased expression of opsins and decreased the numbers of each cone type.
- Van Camp et al. (2019) showed that deiodinase 2 knockout in zebrafish (expected to result in decreased levels of T3) reduced the numbers of red (long-wavelength-sensitive)/green (medium-wavelength-sensitive) cones and rods.
- Mackin et al. (2019):
  - Fluorescent lws reporters permitted direct visualization of individual cones switching expression from lws2 to lws1 (with longer wavelength sensitivity) in zebrafish treated with TH.
  - Athyroidism increased lws2 and reduced lws1, except within a small ventral domain of lws1 that was likely sustained by retinoic acid signaling.
  - Changes in lws abundance and distribution in athyroid zebrafish were rescued by TH, demonstrating essentiality of decreased TH levels for the downstream effect of altered photoreceptor patterning, and demonstrating plasticity of cone phenotype.
  - The intracellular presence of T3 was consistent with the fraction of LWS cones that switch from lws2 to lws1 expression, supporting the importance of T3.
  - In juvenile zebrafish treated with T4, transcript abundance of both short-wavelength-sensitive opsins sws1 (UV opsin) and sws2 (blue opsin) was reduced.
  - TH treatment also regulated the rh2 (medium-wavelength-sensitive, green cone) array, with athyroidism reducing abundance of distal members that are sensitive to longer wavelengths.
winter flounder, a species that undergoes metamorphosis:
- Mader and Cameron (2006): TH signaling significantly affects, in a targeted manner, the photoreceptor pattern during retinal growth and regeneration. More specifically, evidence suggests that TH is required for specification of rods (i.e. manifestation of the rod as opposed to cone photoreceptor lineage), while TH influences the differentiation (i.e., expression of particular opsins), but perhaps not specification, of cone photoreceptors.

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

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

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Taxonomic 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).
Life-stage applicability
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.
Sex applicability
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.

References

List of the literature that was cited for this KER description. More help

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.