期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 26, 页码 15262-15269出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1920086117
关键词
thyroid hormone; retinal development; cone photoreceptors; vitamin A(2); zebrafish
资金
- National Institutes of Health [EY024958, EY025196, EY026672, EY025696, EY027387, GM122471]
Thyroid hormone (TH) signaling plays an important role in the regulation of long-wavelength vision in vertebrates. In the retina, thyroid hormone receptor beta (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.
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