Thyroid hormone receptors mediate two distinct mechanisms of long-wavelength vision

Abstract

<jats:p>Thyroid hormone (TH) signaling plays an important role in the regulation of long-wavelength vision in vertebrates. In the retina,<jats:italic>thyroid hormone receptor β</jats:italic>(<jats:italic>thrb</jats:italic>) is required for expression of long-wavelength-sensitive opsin (<jats:italic>lws</jats:italic>) in red cone photoreceptors, while in retinal pigment epithelium (RPE), TH regulates expression of a cytochrome P450 enzyme,<jats:italic>cyp27c1</jats:italic>, that converts vitamin A<jats:sub>1</jats:sub>into vitamin A<jats:sub>2</jats:sub>to produce a red-shifted chromophore. To better understand how TH controls these processes, we analyzed the phenotype of zebrafish with mutations in the three known TH nuclear receptor transcription factors (<jats:italic>thraa</jats:italic>,<jats:italic>thrab</jats:italic>,<jats:italic>and thrb</jats:italic>). We found that no single TH nuclear receptor is required for TH-mediated induction of<jats:italic>cyp27c1</jats:italic>but that deletion of all three (<jats:italic>thraa</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup><jats:italic>;thrab</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup><jats:italic>;thrb</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup>) completely abrogates its induction and the resulting conversion of A<jats:sub>1</jats:sub>- to A<jats:sub>2</jats:sub>-based retinoids. In the retina, loss of<jats:italic>thrb</jats:italic>resulted in an absence of red cones at both larval and adult stages without disruption of the underlying cone mosaic. RNA-sequencing analysis revealed significant down-regulation of only five genes in adult<jats:italic>thrb</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup>retina, of which three (<jats:italic>lws1</jats:italic>,<jats:italic>lws2</jats:italic>, and<jats:italic>miR-726</jats:italic>) occur in a single syntenic cluster. In the<jats:italic>thrb</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup>retina, retinal progenitors destined to become red cones were transfated into ultraviolet (UV) cones and horizontal cells. Taken together, our findings demonstrate cooperative regulation of<jats:italic>cyp27c1</jats:italic>by TH receptors and a requirement for<jats:italic>thrb</jats:italic>in red cone fate determination. Thus, TH signaling coordinately regulates both spectral sensitivity and sensory plasticity.</jats:p>

Foxq2 determines blue cone identity in zebrafish

“…1H) manifested a massive reduction of both lws1 and lws2 expression and a concomitant increase in sws1 expression in the larval eyes ( Fig. 1I) as reported in previous studies (16,(26)(27)(28). We noticed that thrb ja27 mutant exhibited a moderate but significant increase in sws2 gene expression ( Fig.…”

Mechanistic insights into the evolution of the differential expression of tandemly arrayed cone opsin genes in zebrafish

“…Several trans‐regulatory factors have been identified as critical regulators for the cell type‐specific expression of opsin genes in zebrafish. Thyroid hormone (TH) receptor B ( thrb ) is required for LWS expression (DuVal & Allison, 2018; Suzuki et al, 2013; Volkov et al, 2020), and the transcription factor Tbx2b is essential for SWS1 expression (Alvarez‐Delfin et al, 2009). Also, it was shown that six6 and six7 regulate the expression of SWS2 and RH2 genes (Ogawa et al, 2019; 2015).…”

“…It is also possible that other transcription factors induced by RA and TH affect LWS expression. A recent transcriptomic analysis in zebrafish retinas upon the knockout of thrb found only five genes are down‐regulated, among which three (LWS‐1, LWS‐2, and miR‐726, a conserved microRNA gene located between SWS2 and LAR) are from the LWS locus (Volkov et al, 2020). These results may indicate that the TH receptor directly regulates LWS expression.…”

“…These results may indicate that the TH receptor directly regulates LWS expression. However, it should be noted that knockout and knockdown of thrb result in nearly complete loss of the red cones, LDCs (DuVal & Allison, 2018; Suzuki et al, 2013; Volkov et al, 2020). Therefore, it remains elusive how the receptor controls LWS expression in LDCs.…”

Thyroid hormone regulates abrupt skin morphogenesis during zebrafish postembryonic development

“…In vertebrates, thyroid hormone (TH) is a key regulator of postembryonic development (Laudet, 2011; McMenamin and Parichy, 2013; Tata, 1998). TH is necessary and sufficient for all aspects of amphibian metamorphosis (Tata, 1998) and has been shown to regulate development of the adult pigment pattern, pancreas, skeleton and nervous system in the zebrafish (Hu et al, 2020; Hu et al, 2019; Hur et al, 2017; Matsuda et al, 2017; McMenamin et al, 2014; Saunders et al, 2019; Volkov et al, 2020). One of the many important TH target organs in human is the skin.…”