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

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