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

Abstract

Thyroid hormone (TH) signaling plays an important role in the regulation of long-wavelength vision in vertebrates. In the retina, <i>thyroid hormone receptor β</i> (<i>thrb</i>) is required for expression of long-wavelength-sensitive opsin (<i>lws</i>) in red cone photoreceptors, while in retinal pigment epithelium (RPE), TH regulates expression of a cytochrome P450 enzyme, <i>cyp27c1</i>, that converts vitamin A₁ into vitamin A₂ 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 (<i>thraa</i>, <i>thrab</i>, <i>and thrb</i>). We found that no single TH nuclear receptor is required for TH-mediated induction of <i>cyp27c1</i> but that deletion of all three (<i>thraa</i>^<i>-/-</i><i>;thrab</i>^<i>-/-</i><i>;thrb</i>^<i>-/-</i> ) completely abrogates its induction and the resulting conversion of A₁- to A₂-based retinoids. In the retina, loss of <i>thrb</i> 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 <i>thrb</i>^<i>-/-</i> retina, of which three (<i>lws1</i>, <i>lws2</i>, and <i>miR-726</i>) occur in a single syntenic cluster. In the <i>thrb</i>^<i>-/-</i> 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 <i>cyp27c1</i> by TH receptors and a requirement for <i>thrb</i> in red cone fate determination. Thus, TH signaling coordinately regulates both spectral sensitivity and sensory plasticity.