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, thyroid hormone receptor β ( thrb ) is required for expression of long-wavelength-sensitive opsin ( lws ) in red cone photoreceptors, while in retinal pigment epithelium (RPE), TH regulates expression of a cytochrome P450 enzyme, cyp27c1 , that converts vitamin A 1 into vitamin A 2 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 ( thraa , thrab , and thrb ). We found that no single TH nuclear receptor is required for TH-mediated induction of cyp27c1 but that deletion of all three ( thraa −/− ;thrab −/− ;thrb −/− ) completely abrogates its induction and the resulting conversion of A 1 - to A 2 -based retinoids. In the retina, loss of thrb 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 thrb −/− retina, of which three ( lws1 , lws2 , and miR-726 ) occur in a single syntenic cluster. In the thrb −/− 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 cyp27c1 by TH receptors and a requirement for thrb in red cone fate determination. Thus, TH signaling coordinately regulates both spectral sensitivity and sensory plasticity.