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

<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>