Biphasic expression of thyroid hormone receptor TRβ1 in mammalian retina and anterior ocular tissues

Abstract

The retina is increasingly recognized as a target of thyroid hormone. We previously reported critical functions for thyroid hormone receptor TRβ2, encoded by Thrb, in cones, the photoreceptors that mediate color vision. TRβ1, another Thrb receptor isoform, is widely expressed in other tissues but little studied in the retina. Here, we investigate these N-terminal isoforms by RNA-sequencing analysis and reveal a striking biphasic profile for TRβ1 in mouse and human retina. In contrast to the early TRβ2 peak, TRβ1 peaks later during retinal maturation or later differentiation of human retinal organoids. This switch in receptor expression profiles was confirmed using lacZ reporter mice. TRβ1 localized in cones, amacrine cells and ganglion cells in contrast to the restricted expression of TRβ2 in cones. Intriguingly, TRβ1 was also detected in the retinal pigmented epithelium and in anterior structures in the ciliary margin zone, ciliary body and iris, suggesting novel functions in non-retinal eye tissues. Although TRβ1 was detected in cones, TRβ1-knockout mice displayed only minor changes in opsin photopigment expression and normal electroretinogram responses. Our results suggest that strikingly different temporal and cell-specific controls over TRβ1 and TRβ2 expression may underlie thyroid hormone actions in a range of ocular cell types. The TRβ1 expression pattern suggests novel functions in retinal and non-neural ocular tissues.

Expanding the phenotype of THRB: a range of macular dystrophies as the major clinical manifestations in patients with a dominant splicing variant

“…We hypothesized that the c.283 + 1G>A variant could impact retinal-specific functions mainly involved in cone viability without a major affectation of cone subtype specification that is mediated by TRβ2. In fact, a recent study experimentally demonstrates that TRβ1-knockout mice displayed only minor changes in opsin photopigment expression (Ng et al, 2023), resembling what we observed in our patients. Authors suggest that TRβ1, the predominant TRβ isoform at mature ages, may have a role in the survival of both cone photoreceptors and retinal pigment epithelium cells (Ng et al, 2023), as described in other retinal degeneration models (Ma et al, 2014;Ma et al, 2017;Ma et al, 2022), and now in the IRD patients of our cohort.…”

“…In fact, a recent study experimentally demonstrates that TRβ1-knockout mice displayed only minor changes in opsin photopigment expression (Ng et al, 2023), resembling what we observed in our patients. Authors suggest that TRβ1, the predominant TRβ isoform at mature ages, may have a role in the survival of both cone photoreceptors and retinal pigment epithelium cells (Ng et al, 2023), as described in other retinal degeneration models (Ma et al, 2014;Ma et al, 2017;Ma et al, 2022), and now in the IRD patients of our cohort. Of note, only two putatively pathogenic variants have been identified in the TRβ1 N-terminal domain in patients with congenital hypothyroidism and thyroid dysgenesis (Zhou et al, 2018).…”

Local modulation of thyroid hormone signaling in the retina affects the development of diabetic retinopathy

“…Therefore, decreasing the intraretinal levels of THs may represent a retinal strategy, similar to those involving VEGF overexpression or autophagy activation, to reduce oxidative stress and cell damage under hyperglycemic condition. Even though this compelling hypothesis has never been investigated, the presence of TH receptors [10][11][12], of the monocarboxylate transporter 8 [13], of TH responsive cells [14], and of deiodinase enzymes [15,16] in the retina suggests the possibility of a retinal, local regulation of the TH system to reduce retinal stress. For instance, anti-TH treatments in experimental models of congenital retinal diseases have been observed to protect cone photoreceptors from degeneration [17][18][19].…”