Thyroid hormone receptor beta mutations alter photoreceptor development and function in Danio rerio (zebrafish)

Abstract

We investigate a splice variant of thrb isolated in the retina, tr{beta}2, identifying functional changes in larval and adult mutant zebrafish lacking tr{beta}2. We constructed two CRISPR mutant zebrafish with mutations located in the N-terminus region. The first is a 6BP+1 insertion deletion frameshift resulting in a truncated protein. The second is a 3BP in frame deletion with intact binding domains. ERG recordings showed that the 6BP+1 mutants did not respond to red wavelengths of light while the 3BP mutants did respond. 6BP+1 mutants lacked optomotor and optokinetic responses to red/black and green/black contrasts. Adult 6BP+1 mutants exhibit a loss of red-cone contribution to the ERG, and an increase in green and UV contributions. Anatomical markers show loss of red-cones in the 6BP+1 mutant but increase in blue, green, and UV cone density. Our results confirm tr{beta}2s role in retinal cone development.\n\nAuthor SummaryThere are four cone photoreceptors responsible for color vision in zebrafish: red, green, blue, and UV. The thyroid hormone receptor tr{beta}2 is localized in the vertebrate retina. We know that it is necessary for the development of long-wavelength-sensitive cones (red), but here we investigate the functional alterations that accompany a loss of tr{beta}2. Our work contributes to the ongoing investigations of retinal development and the involvement of thyroid hormone receptors. Confirming previous morphological findings, we see that the fish become red colorblind when tr{beta}2 is knocked out, but the contributions of the other three cone types shift in response. Our work highlights the plasticity of the retinal circuit as we see changes in opsin peaks and cone sensitivity, increases in contributions of UV cones, and an attempt at a mosaic pattern in the adult retina all in the absence of tr{beta}2 and red cones. We now have an increased understanding of mechanisms underlying retinal development