Abstract
A growing body of evidence has established that thyroid hormone (triiodothyronine, T3) is a key factor in the differentiation and survival of the light-sensing photoreceptors in the retina. These functions include a critical role in generating the cone photoreceptor diversity that is required for color vision. Here, we review some of these functions of T3 and the critical mechanisms that regulate the T3 signal in the mammalian retina. The provision of T3, the active form of thyroid hormone, is determined by developmentally rising levels of T3 and its precursor T4 (thyroxine) in the circulation and by intrinsic control within the retina itself by deiodinase enzymes that deplete or amplify the available level of T3. Dynamic profiles of inactivating (DIO3) and activating (DIO2) deiodinases suggest that the T3 signal is progressively calibrated throughout early development, maturation and later functional maintenance of the retina. However, the benefits of T3 come at a cost: photoreceptors are susceptible to impairment and cell death when T3 signaling becomes imbalanced. These findings have implications regarding the influence of T3 in retinal diseases.
Introduction
In the visual system, the photoreceptors that mediate vision are major targets of T3 signaling. The mammalian retina contains cone photoreceptors that mediate high-acuity vision in daylight and chromatic (i.e., color) vision, as well as rod photoreceptors that mediate vision in dim light conditions. Early studies of T3 receptor expression patterns in the retina indicated that photoreceptors are direct targets of T3 action (1, 2). Further studies that manipulated either the receptors or thyroid hormone levels have since indicated a major role for T3 in the differentiation and maintenance of cone photoreceptors (e.g. (2, 3, 4, 5, 6, 7, 8)) and a lesser contribution to the maintenance of rod photoreceptors (5, 7, 9). Ongoing research is likely to reveal functions of T3 in other retinal cell types.
In addition to T3 and T4 in the circulation, deiodinase enzymes within target tissues can modify T3 levels in the local environment: type 2 deiodinase (DIO2) amplifies and type 3 deiodinase (DIO3) depletes T3 levels (10, 11). Both DIO2 and DIO3 enzyme activities are present in the retina (5, 12, 13). Studies 40 years ago (12) reported a dramatic switch in these two opposing deiodination activities during rat retinal maturation, suggesting dynamic control over the T3 signal throughout retinal development. As will be discussed, deiodinase enzymes control the maturation and survival of photoreceptors, especially cone photoreceptors.
Other factors contribute to T3 signaling but are not the main focus of this article. Membrane transporters (14, 15) are thought to be required to transfer T3 and T4 across the blood-retina barrier (16, 17) and into retinal cell types (18, 19, 20). MCT8, a transporter in the retinal pigment epithelium that forms the outer blood-retina barrier, has been reported to control cone differentiation (20). Ultimately, cellular responses are mediated by T3 receptors, which are nuclear receptor transcription factors (21, 22). The THRB receptor gene encodes TRβ1 and TRβ2 receptor isoforms, and THRA encodes a TRα1 isoform, which are differentially expressed in the retina (2, 23). THRB has major functions in cone diversity and maturation in mice (2, 4, 5), retinal organoids (8) and human patients (24, 25). T3 receptors are a key component of the gene regulation network that directs the differentiation of cone and rod photoreceptor types, as has been discussed elsewhere (26, 27, 28, 29, 30).
In this review, we discuss the functions of T3, deiodinase-mediated mechanisms of control of the T3 signal and the consequences of aberrant T3 signaling in the mammalian retina. It has become apparent that the benefits bestowed by T3 on the retina are accompanied by an inherent risk because imbalanced T3 signaling can impair the differentiation and survival of photoreceptors. Accordingly, we discuss the implications of T3 as a factor in retinal disease. We also note gaps in understanding that merit attention, as knowledge of the functions of T3 in the retina is far from complete.
Systemic and tissue-intrinsic control of T3 in the retina
The thyroid gland produces T3, the active form of thyroid hormone, and thyroxine (T4), a more abundant precursor that can be converted into T3. The developmental rise of T3 and T4 in the circulation provides a systemic stimulus for the maturation of many tissues (Fig. 1), as is evident from the impairments associated with human developmental hypothyroidism or disorders arising from an endemic deficiency of iodine, an essential component of thyroid hormone (31, 32, 33). Studies of rodent models have indicated that the retina is a T3-dependent tissue (Fig. 1) (Table 1). The finding of type 3 (inactivating, DIO3) and type 2 (activating, DIO2) deiodination activities in the retina (5, 12, 13) indicated that the retina itself can modify T3 availability. DIO2 generates T3 by removal of iodine from the outer ring of T4, whereas DIO3 depletes both T4 and T3 by removal of iodine from the inner ring of each form of the hormone (10, 11) (Fig. 2). Deiodinase proteins incorporate the rare amino acid selenocysteine and belong to the class of selenoenzymes (34).
Systemic and tissue-intrinsic regulation of T3 in the retina. (A) T4 and T3 in the circulation rise during development, and in mice, peak around the second postnatal week then stabilize in adulthood (128, 129). An early peak of DIO3 activity protects the immature retina from excessive exposure to T3. DIO2 rises during later retinal differentiation as DIO3 declines and could amplify T3 levels. A predicted net rise in T3 signaling encompasses terminal differentiation and maturation of visual function. (B) The developmental switch of Dio3 and Dio2 expression is detected in RNA-seq datasets of mouse (23) (pools of retinas) and human retina (58, 130) (each point from a single individual). A similar trend is detected in retinal organoids derived from human H9 embryonic stem cells (131). DIO1 RNA is undetectable at any stage. Analysis of datasets with GEO accession numbers: mouse GSE 224863; human fetal GSE 104827; human adult peripheral retinal punches GSE 115828; human retinal organoids GSE 129104.
Citation: European Thyroid Journal 14, 2; 10.1530/ETJ-24-0315
Photoreceptor/retinal responses in hypothyroid and hyperthyroid conditions.
| Thyroid status/species | Photoreceptor/ocular changes | Treatment, severity and stage | Reference |
|---|---|---|---|
| Hypothyroid in development | |||
| Mouse | Impair M opsin expression, partial shift of M to S cone identity; retard retinal transcriptome | MMI, severe, gestational/postnatal or genetic Tshr-KO, Pax8-KO | (4, 20, 28, 48, 49) |
| Rat | Impair M opsin expression, partial shift of M to S cone identity | MMI, severe, gestational/postnatal | (49) |
| Rat | Reduction of M cone ERG, modest | PTU, moderate, gestational/postnatal | (50) |
| Rat | Craniofacial malformation, small eyeball, thin retinal layers, delayed opening of eyes; reduced ganglion cell density | PTU/neonatal thyroidectomy in offspring or PTU alone; severe, gestational/postnatal | (53, 54, 55, 56) |
| Mouse | Alleviate loss of cones in models of retinal degeneration | MMI, postnatal/juvenile, severe; in models of achromatopsia (Cpfl1, Pde6c-KO) and Leber congenital amaurosis (Rpe65-KO) | (7) |
| Mouse | Alleviate damage in chemically-induced model of RPE/retina degeneration | MMI, juvenile-young adult treatment then sodium iodate to induce RPE/retinal damage in model of ‘macular’ degeneration | (91, 92) |
| Hypothyroid in adulthood | |||
| Rat, mouse | Impair M opsin expression, partial shift of M to S cone identity | MMI, adult, severe, prolonged (∼2 months or longer treatment) | (6) |
| Rat | Mild delay of ERG b-wave, dark-adapted (rod); reduced renewal of outer segments | Thyroidectomy, adult, severe, 2 weeks before analysis | (68, 69) |
| Hyperthyroid | |||
| Mouse | Neonate: severe loss of cones (M and S types), achromatopsia | T3, neonatal, severe or genetic (Dio3-KO) | (5, 13) |
| Mouse | Juvenile-young adult: partial loss of cones and rods, induce transcriptome pathways of oxidative stress/inflammation/necroptosis in retina | T3, juvenile-young adult, severe extremely high T3 doses, chronic treatment | (9, 71) |
| Mouse | Exacerbate loss of cones and rods in retinal degeneration | T3, postnatal, severe, treatment of models: achromatopsia, Cngb3-KO; Leber congenital amaurosis, Gucy2e-KO | (7) |
| Mouse | Partly suppress S opsin, restore M/S patterns in hypothyroid model | T3, neonatal; T4 , Pax8-KO (hypothyroid), postnatal | (3, 6) |
ERG, electroretinogram; MMI, methimazole; PTU, propylthiouracil; RPE, retinal pigment epithelium.
Scheme indicating sources of T4 and T3 for the retina. (A) In the circulation, T3, the primary active form of thyroid hormone, and its precursor T4 are present with T3 at relatively low concentrations. Within the retina, DIO2 generates T3 by conversion from T4. DIO3 converts both T4 and T3 into the largely inactive metabolites reverse T3 (rT3) and 3,3′-diiodothyronine (T2), respectively. Plasma membrane transporters mediate uptake of T3 and T4 into the retina, requiring transfer across the blood-retina barrier. An outer barrier is formed by the RPE adjacent to the fenestrated vessels in the choroid. An inner barrier is formed by the tight junctional barrier of inner retinal vessels. (B) Histological section of the adult mouse retina. The photoreceptor layer contains cones (large nuclei with dispersed heterochromatin), which align near the outer zone of the layer, and more numerous rods (smaller nuclei with dense heterochromatin). Rods are >30-fold more abundant than cones in mice (132). The photoreceptor layer is non-vascularized. The photoreceptor segments extend to the microvilli of the RPE (i.e. the outer blood-retina barrier). Scale bar 25 μm.
Citation: European Thyroid Journal 14, 2; 10.1530/ETJ-24-0315
The successive developmental peaks of DIO3 and then DIO2 in the retina indicate that the tissue progresses from a state of constrained T3 signaling to a state of more active T3 signaling (5, 12, 13) (Fig. 1). The decline of DIO3 reduces the degradation of T3, while the rise of DIO2 can amplify T3 in the retina, augmenting the T3 available from circulation (35). At each stage, the level of T3 must be kept within limits, as excessive T3 causes loss of photoreceptors (5, 7, 9) and potentially other defects in the retina. The early DIO3 peak protects immature cones from T3-induced cell death but does not necessarily indicate a complete block of T3 action. Low levels of T3 present in the fetus may serve as yet undefined roles in ocular tissues and the development of vision. During the first half of human gestation, before the fetal thyroid gland becomes active, maternal thyroid hormone is thought to promote other neurodevelopmental outcomes in the offspring, such as cognitive function (36, 37) and hearing (32, 38).
The DIO3/DIO2 activity profiles in retinal development have been supported by northern blot (5, 13) and RNA-sequencing analyses (13, 23) (Fig. 1B). Similar RNA-seq profiles are found for the human retina (23) and retinal organoids in culture (8, 23). DIO1, a deiodinase with functions in the liver and kidney (39), has not been detected in the mammalian retina.
T3 and cone photoreceptor development
In most mammals, color vision is determined by distinct cone populations that differentially express M or S opsin photopigments for sensitivity to medium (M, green) and short (S, blue) wavelengths of light, respectively (40, 41, 42). A profound action of T3 in determining this cone photoreceptor diversity was indicated by the deletion of TRβ2, a rare cone-specific T3 receptor isoform encoded by Thrb, which resulted in a form of blue monochromatic color blindness in mice (2). In TRβ2-KO mice, M cones are absent, and all cones become S-type, indicating that TRβ2 directs M or S outcomes from cone precursors with a default S opsin identity. TRβ2 induces M opsin and differentially patterns M and S opsins, which requires suppression of S opsin in a subpopulation of cones (2, 28, 30). The sensitivity of this control is evident from noncoding Thrb mutations in mice that partly reduce TRβ2 levels and impair M cone electroretinogram responses (43).
Thrb differentially expresses TRβ2 and TRβ1 isoforms in the retina, with TRβ2 specifically in cones (2) whereas TRβ1 is expressed later in cones and in other retinal cell types (23). A similar cone opsin phenotype as occurs in TRβ2-KO mice has been reported in mice with total deletion of Thrb (2) and in mice homozygous for dominant negative mutations in Thrb (3, 4, 44). Only a minimal cone phenotype has been reported in mice with the deletion of the TRβ1 isoform (23). A transcriptional mechanism underlying cone diversity has been supported by finding TRβ2-regulated chromatin sites in cones and the elucidation of the TRβ2-regulated transcriptome in M- and S-type cone populations in mice (30).
Hormonal manipulations
Cones are generated by the time of birth in rodents (45, 46) and then acquire M and S identities over the next 2–3 weeks of maturation (30, 47) as T4 and T3 levels rise (Fig. 1). Developmental hypothyroidism in rodents impairs both the expression of M opsin and the suppression of S opsin (4, 28, 48, 49) and impairs M cone electroretinogram responses (50), resembling the TRβ2-KO phenotype (Table 1). The severity varies due to experimental design and technical differences but is not as extreme as that in the absence of TRβ2, which can be explained by residual levels of T3 and T4 being able to promote a slow, partial catch-up of cone development. Hyperthyroidism due to treatment with T3 leads to cone loss (5, 7, 9) (Table 1), although limited exposure (3) or treatment with T4 instead (6) modifies M and S opsin expression levels. The outcome depends on dose, duration, age when treated and whether T4 or T3 is given. Immature cones are more susceptible than mature cones to cell death. T3, the ligand for the receptor, gives a more immediate and severe response than T4, which must first be converted to T3, a regulated physiological process that cushions the impact of treatment with T4.
A role for maternal thyroid hormone was suggested in a study of female mice with hypothyroidism during pregnancy and nursing (51). The offspring had a transient delay in M opsin expression, implicating maternal hormone in initiating M opsin expression. As discussed below, maternal thyroid hormone may play a much greater role in human cone diversity, as opsin patterning is largely established in fetal development in humans but postnatally in mice (27, 52) (Fig. 3).
Functions of T3 in retinal development and disease. (A) Cone development progresses earlier in humans than in mice relative to the time of birth. The time scales differ, with mice born at ∼20 days and humans at ∼40 weeks post-conception. Cones are generated during early gestation in humans (52, 57, 58) but later gestation in mice (45). Opsin patterning initiates early in utero in humans (23, 52) but is established postnatally in mice (30, 47). Retinal function matures over several weeks in mice and over a period of months or years in humans (57, 133, 134). (B) T3 regulates the development and maintenance of the retina and could potentially modify the pathogenesis of different retinal diseases. Retinal disorders due to genetic defects in T3 signaling are very rare (see text for discussion). However, evidence suggests that T3 could modify the outcomes of more common retinal disorders arising from other causes.
Citation: European Thyroid Journal 14, 2; 10.1530/ETJ-24-0315
Apart from opsin expression patterns, severe gestational hypothyroidism in rat models has been reported to produce additional changes in craniofacial and eyeball morphology and in retinal cell layer densities (53, 54, 55, 56), suggesting additional roles of T3 in ocular development.
T3 and human cone photoreceptor diversity
A role for T3 in generating human cone diversity was strongly suggested in a notable study of human retinal organoids in culture, in which T3 induced the expression of medium-long wavelength-sensitive (M/L) opsins and suppressed S opsin (8). These actions required the THRB gene, as in mice. M/L opsins failed to be expressed in THRB-deficient organoids. However, for a variety of reasons, including a paucity of specific studies, it remains a challenge to conclude that a related role for T3 is involved in human cone diversity in vivo. Cone opsin patterning is initiated in the first half of human gestation (23, 52, 57, 58) and is presumably promoted by maternal thyroid hormone before the fetal thyroid gland becomes active (Fig. 3). Even if a fetus lacks a functional thyroid gland and the infant will be born with congenital hypothyroidism, maternal hormone may suffice to establish opsin patterning during the sensitive period in utero. This maternal source of hormone may avert obvious opsin-based cone defects (e.g. monochromacy) in infants born with this condition.
A few studies of human resistance to thyroid hormone, a rare syndrome due to THRB mutations, have reported impaired responses to medium-long wavelength (red) stimuli (24, 25) and monochromacy (59), reminiscent of the phenotype in TRβ2-KO mice (2). Although homozygous THRB inactivation results in dramatic shifts in M/L to S cone identity in human retinal organoids (8) or mice (2), most THRB mutations in human patients are heterozygous and have been associated with relatively mild impairment of M/L cone (long wavelength) responses in electroretinogram analyses (25). Support for a conserved role in human cone diversity in vivo would be aided by specific investigations of cone types and opsins in human subjects who carry a complete (i.e. homozygous) loss of the THRB receptor gene, if such exceptionally rare cases were to be found. It may also be worth investigating individuals who experienced early-onset thyroid defects during the critical fetal period of opsin patterning, for example, as can arise in areas of endemic iodine deficiency (32).
T3 and photoreceptor maintenance at mature ages
Maintenance of M and S cone identities
The retina can respond to T3 at mature ages, although this question has been less studied and has less obvious findings than at developmental stages. However, a remarkable finding was that M and S opsin patterning can be altered by prolonged, severe hypothyroidism in adult rats or mice (6). Adult-onset hypothyroidism diminished M opsin expression and derepressed S opsin, whereas administration of T4 restored M and S opsin patterning, suggesting that thyroid hormone is continuously required to maintain M and S cone identities. Although the phenotypic and epigenetic status of neurons is thought to stabilize during terminal differentiation, cones retain latent plasticity that can be activated with lengthy changes in thyroid hormone status. This response might be mediated by the low levels of TRβ2 in the adult retina (60) or by the expression of TRβ1 in mature cones (23). The opsin patterning shift was shown after prolonged hypothyroidism (over months), implying that it is difficult to force changes in cone identities at mature stages. Mammalian color vision requires a stable complement of cone types; that is, opsin patterning should not fluctuate with erratic changes in thyroid hormone levels. Indeed, color blindness is not remarked upon in routine examinations for adult human hypothyroidism, and in a few exploratory studies, overt changes in color visual perception were not noted (61, 62, 63). Minor changes suggested in contrast sensitivity relied on tests of response choices by patients without direct analyses of retinal opsins or cone function.
A limited degree of control of opsin RNA levels by thyroid hormone at more mature stages has been reported in some species with specialized lifestyles, namely the subterranean Ansell mole rat (64) and certain fish species (65, 66, 67). These observations suggest that T3 mediates partial control of opsin expression at mature stages in some species with adaptations to specialized habitats.
Maintenance and survival of photoreceptors
Several observations suggest additional functions for T3 in mature photoreceptors. High-resolution single-cone analyses indicate that TRβ2 regulates a limited group of cone diversity genes, including M and S opsin genes, but also a second, larger group of maturational genes common to all cone types in mice (30). This latter group of genes merits further investigation, as it may yield insights into mature cone function. In adult rats, adult-onset hypothyroidism has been reported to delay darkness-adapted electroretinogram responses and to diminish the renewal of photoreceptor outer segments (68, 69) suggesting actions of T3 in photoreceptor homeostasis. In a study of three hypothyroid adult dogs, T4 treatment was reported to shorten photopic and scotopic electroretinogram responses (70). Very high doses of T3 given for a prolonged period (1 month) to juvenile-young adult mice altered the expression of genes for oxidative stress, inflammatory response and necroptosis (9, 71), suggesting pathways that respond to excessive T3 at more mature ages.
Regarding T3 and photoreceptor survival, Dio3-KO mice, which lack protection from T3, have severe loss of cones, mild loss of rods and corresponding impairments of electroretinogram responses (5, 13). Very high doses of T3 given to young adult mice also cause partial loss of cones and rods with a reduction of electroretinogram responses (9). Such responses in the mature retina may be mediated by TRα1 or TRβ1 receptors encoded by Thra and Thrb genes, respectively, which are more widely expressed than TRβ2. Deletion of TRα1 makes rods resistant to damage from excessive T3 in young adult mice (9). TRβ1 is expressed in human and mouse retina and is detected in cones, rods, amacrine cells and ganglion cells in mice (23). It is not excluded that defects in cones indirectly contribute to subtler impairments in rods.
Deiodinases and paracrine-like control of T3 in the retina
The dynamic decrease of DIO3 and rise of DIO2 during retinal maturation (Fig. 1) coincide with M opsin induction, which initially suggested a major role for deiodinases in determining opsin expression patterns and cone diversity. However, studies of Dio3-KO mice indicated instead that DIO3 safeguards the survival of cones by limiting exposure to T3 to avoid triggering an apoptosis-inducing action of TRβ2 (5). A survival role is consistent with protective roles of DIO3 in other tissues such as the cochlea (38), testis (72) and muscle (73). Dio3 is expressed in undifferentiated retinal progenitor cells in embryonic and neonatal mice (5) (Fig. 4), creating a cellular ‘sink’ that could limit exposure of vulnerable cones to T3 by paracrine-like control. A similar paracrine-like protective role has been proposed for DIO3 in limiting T3 for Sertoli cells in the testis (74).
Deiodinases and cell-to-cell control of T3 availability for cones. (A) Image of Dio3 expression in undifferentiated progenitor cells and diagram (on right) suggesting that DIO3 protects cones from excessive T3 in the immature mouse retina (embryonic day 17 shown). Some T3 is needed for initiation of M opsin expression and opsin patterning, but excessive T3 triggers cone cell death. Retinal progenitor cells generate a variety of retinal cell types and are intermingled with newly formed cones. In a proposed model, Dio3-expressing cells form a protective ‘sink’ that degrades T3, constraining exposure to T3. DIO3 also depletes T4, although this is not shown for simplicity. Scale bar 20 μm. (B) At later stages, DIO2 in Müller glial cells can amplify T3 levels in the juvenile and adult mouse retina. Müller glial extensions can transport solutes, potentially including T3, to cones and other cell types. Other possible routes of transport of T3 (such as transfer of blood-borne T3 through the RPE) are not shown in this simplified scheme. Confocal microscopy images: Lily Ng and Ye Liu, using cre drivers for Dio2 (79) and Dio3 (Y Liu, personal communicaion) with an Ai6 fluorescent reporter (pale blue). Scale bar 25 μm.
Citation: European Thyroid Journal 14, 2; 10.1530/ETJ-24-0315
The rise of DIO2 activity in the retina coincides with the rising expression of M opsin (13) but also with many maturational genes in cones (30). Deletion of DIO2 did not block M opsin expression and was reported to give little or no change of S opsin in one study (13) and only a partial increase of S opsin in a sub-domain of the dorsal retina in another study (75). So, what might be other purposes of the postnatal rise of DIO2? A study has reported that DIO2 in Müller glial cells aids in adaptation to light (76), potentially optimizing the photoresponse of cones in mice. Adaptation to changing light intensities involves complex adjustments that allow cones to function over a range of light conditions (77). By studying light and darkness adaptation over a 3 h period, Dio2 expression was reported to be increased by light and to stimulate oxidative metabolism in retinal explants. In Dio2-KO mice, photoresponses decreased, suggesting that DIO2 in Müller glia supports cone metabolism during adaptation to light.
Thus, Müller glia could provide T3 (a paracrine-like signal) locally (Fig. 4B), supplementing the T3 available from circulation (an endocrine signal). Paracrine-like control has also been proposed for DIO2 in glia in the brain in providing T3 for neurons (78) and in fibrocytes in the cochlea in providing T3 for the organ of Corti (79). T3 generated by DIO2 in Müller glia might also stimulate rods or other retinal cell types. Müller glia projections extend across the retinal layers, allowing transport of solutes to different cell types (80) (Fig. 4). A study suggested circadian control of Dio2 in cones, although without direct detection of Dio2 expression in cones (75). The proposed expression in cones is inconsistent with the detection of Dio2 expression reported in Müller glia by in situ hybridization (13, 76), microarray (81) and single-cell analyses of mouse (76) and human retina (82). Nor is deiodinase expression detected by high-resolution single-cone RNA-sequencing in mice (23), supporting the view that cones respond to deiodination occurring in other retinal cell types. Although it is challenging to map the cellular localization of deiodinases because of low-level, transient profiles, the location of DIO3 and DIO2 in retinal progenitor cells and Müller glia, respectively, is also supported using Cre drivers in Dio3 and Dio2 genes to activate fluorescent reporters (79) (Y Liu, personal communication) (Fig. 4).
A picture is emerging in which DIO3 and DIO2 participate in a network of cell-to-cell communication that modifies T3 signaling for specific retinal cell types, involving both endocrine and local paracrine-like control. Combined endocrine and paracrine-like control was also suggested in a study of Dio2;Dio3 double-knockout mice, in which cone loss due to the absence of DIO3 was rescued by deletion of DIO2 (13). A cellular network model would also involve transporters for the uptake and passage of T4 and T3 to retinal cell types (20) (Fig. 2). Although deiodinase expression patterns are largely programmed in development, Dio3 and Dio2 RNA levels in the retina can respond to changes in thyroid hormone status at mature ages (6). Thus, although levels are low, deiodinases may contribute to reactive or stress responses in the retina.
Differentiation versus dysfunction: balancing good and bad outcomes
A recurrent theme is that the T3 signal in the retina must be carefully calibrated to achieve desirable rather than undesirable outcomes. For example, T3 promotes M and S cone diversity, but excessive T3 causes apoptotic loss of cones (5, 9). Deleterious outcomes may be provoked at any stage in the retinal lifetime, although with varying severity. The lesser susceptibility at older ages could reflect changes that, for example, restrict transport of T3 in the mature retina or epigenetic constraints on the regulation of certain target genes at mature ages. Nonetheless, the persistent vulnerability of photoreceptors to aberrant T3 signaling (9) has implications in retinal disease, as discussed below.
Thyroid hormone and human retinal disorders
Diverse genetic and environmental factors make photoreceptors susceptible to degeneration in retinal disease (83, 84, 85). T3 has traditionally received little attention as a factor, in part due to the scarcity of mutations in genes that mediate T3 signaling and the paucity of analyses of photoreceptors in such cases. THRB receptor gene mutations are rare, but in a few cases, they have been associated with cone impairments in syndromic resistance to thyroid hormone (24, 25, 59) and non-syndromic retinal dystrophy (86). THRA mutations are rare (87), and retinal studies have not been reported. MCT8 transporter mutations are associated with X-linked syndromic psychomotor impairment (15, 88), but retinal analyses are lacking, although studies in mice indicate a role in cone differentiation (20). To date, human DIO3 and DIO2 mutations have not been reported.
Although genetic defects in T3 signaling are a very rare cause of retinal disease, the latent susceptibility of photoreceptors to damage by excessive T3 (5, 9) raises the possibility that T3 is a modifier of more common retinal disorders arising from other defects. In mouse retinal degeneration models, decreased exposure to T3 can partly alleviate photoreceptor loss, whereas elevated T3 pushes photoreceptors further into degeneration (Fig. 3B). Thus, in models of Leber congenital amaurosis (Rpe65-KO) and achromatopsia (Cpfl1 mutant), cone loss is diminished by experimentally induced hypothyroidism (7, 89) or deletion of Thrb (90), whereas cone and rod loss in degenerative models is exacerbated by treatment with T3 (7).
Hypothyroidism may reduce damage to the RPE (retinal pigment epithelium) as well as the retina in a chemically induced model of ‘macular’ degeneration (although mice lack a macula) (91, 92). Human macular degeneration is a leading cause of age-related loss of vision, involving pathogenic damage to the RPE and photoreceptors (83). In a mouse model, treatment with sodium iodate caused oxidative stress in the retina and RPE, but prior treatment with methimazole, which causes hypothyroidism, decreased this damage (91). Deletion of Thrb or Thra genes also reduces damage, indicating that T3 receptors are involved at some stage in the response to sodium iodate (92). Human population studies suggest that elevated T4 in the circulation is associated with age-related macular degeneration (93, 94), implicating T4 as a factor in this condition.
A role for T3 in modifying outcomes in retinal degeneration merits study because this may suggest approaches to manipulate T3 levels as a means to reduce photoreceptor loss in disease, as discussed elsewhere (89, 90, 91, 92, 95). A few studies have begun to explore T3 as a factor in conditions such as diabetic retinopathy (96, 97) and retinopathy of prematurity (98, 99, 100). In addition, human retinoblastoma is reported to originate from cone precursor cells that express M opsin, TRβ2 and TRβ1 (101, 102). The primary cause of retinoblastoma is loss of the tumor suppressor RB1, but T3 receptors might contribute to propagation of the tumor (103).
In human adult-onset hypothyroidism, a lack of obvious cone defects is perhaps unsurprising, given that the most pronounced actions of T3 are in development (e.g., in the generation of cone diversity). Nonetheless, the possibility of minor impairments in adults is not excluded. Although overt changes in opsins are unlikely, other outcomes might include changes in photoreceptor homeostasis and survival.
Coordination of visual system development by T3
T3 coordinates visual development at multiple levels, although this review has focused on the retina. Thyroid hormone can influence central visual processing pathways, and in the rat brain, it modifies latencies of visual-evoked potentials (68, 104) and rates of glucose metabolism in visual centers, including the lateral geniculate body, superior colliculus and occipital cortex (105). In humans, thyroid hormone status may alter latencies of visual-evoked potentials in adults (106, 107) and infants (98, 99). In addition, thyroid hormone promotes developmental opening of the eyes (54, 104, 108) and may act on the RPE, which expresses T3 receptors (23, 109). However, the mechanisms of T3 action at most non-retinal levels of the visual system are poorly defined and require investigation.
T3 and the non-mammalian retina
It is worth noting that certain conserved roles for T3 have been identified in the non-mammalian retina, notably in cone photoreceptor diversity (110, 111, 112, 113). These findings have suggested a common role for T3 in enhancing sensitivity to the green-red regions of the light spectrum in vertebrate species. However, compared to mammals, there are also different functions for T3, reflecting the greater variety of cone types and other adaptations of the eye that occur in fish, amphibian and avian species with widely varying habitats and lifestyles. Further information on this fascinating topic may be found elsewhere (e.g. (1, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123)).
Concluding remarks and some future questions
A fundamental role for T3 in promoting cone photoreceptor diversity has been demonstrated in model species and in organoid cultures in vitro, but additional study is needed to support a conserved role in the human retina in vivo. This question is significant for understanding the cellular basis of human color vision. It may be difficult to find answers unless rare human cases are found with defects (e.g. in receptor or deiodinase genes) that severely impair the functions of T3 during the period of opsin patterning, which occurs in the fetus in human development (23, 52, 57, 58).
The critical chromatin and transcriptional mechanisms by which T3 receptors regulate opsin gene expression to generate cone diversity await detailed elucidation. Regarding retinal disease, it will be valuable to identify how genome-wide control at T3 receptor-regulated chromatin sites (i.e. enhancers) is altered by excessive T3 to cause cone cell death. This will require a deeper understanding of how chromatin-modifying factors and transcription cofactors interact with the T3 receptor to regulate enhancer activity (30).
Photoreceptors in mammals must last a lifetime, enduring challenges of daily exposure to light and high metabolic rates during phototransduction. Information about the functions of T3 in mature photoreceptors is limited, so further study would be rewarding. Most attention has focused on cones and, to some extent, rods, but new target cell types deserve investigation, such as interneurons and ganglion cells (23, 124) (Table 1). Apart from TRβ2, novel functions may be revealed for TRβ1 and TRα1 receptors (2, 23). Understanding the deleterious pathways activated by excessive T3 might suggest treatments that could aid photoreceptor survival in retinal degenerative disorders (7) and illuminate possible impairments in the visual system due to environmental pollutants that act as endocrine-disrupting chemicals (125, 126, 127).
Declaration of interest
The authors have no conflicts of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This work was supported by the intramural research program at NIDDK at the National Institutes of Health.
Author contribution statement
LN and DF prepared the manuscript with input from all authors.
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