TY - JOUR
T1 - Thyroid hormone receptors mediate two distinct mechanisms of long-wavelength vision
AU - Volkov, Leo I.
AU - Kim-Han, Jeong Sook
AU - Saunders, Lauren M.
AU - Poria, Deepak
AU - Hughes, Andrew E.O.
AU - Kefalov, Vladimir J.
AU - Parichy, David M.
AU - Corbo, Joseph C.
N1 - Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/6/30
Y1 - 2020/6/30
N2 - Thyroid hormone (TH) signaling plays an important role in the regulation of long-wavelength vision in vertebrates. In the retina, thyroid hormone receptor (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 A1 into vitamin A2 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 THmediated induction of cyp27c1 but that deletion of all three (thraa/;thrab/;thrb) completely abrogates its induction and the resulting conversion of A1-to A2-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 downregulation 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.
AB - Thyroid hormone (TH) signaling plays an important role in the regulation of long-wavelength vision in vertebrates. In the retina, thyroid hormone receptor (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 A1 into vitamin A2 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 THmediated induction of cyp27c1 but that deletion of all three (thraa/;thrab/;thrb) completely abrogates its induction and the resulting conversion of A1-to A2-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 downregulation 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.
KW - Cone Photoreceptors
KW - Retinal Development
KW - Thyroid hormone
KW - Vitamin A2
KW - Zebrafish
UR - http://www.scopus.com/inward/record.url?scp=85087466923&partnerID=8YFLogxK
U2 - 10.1073/pnas.1920086117
DO - 10.1073/pnas.1920086117
M3 - Article
C2 - 32541022
AN - SCOPUS:85087466923
SN - 0027-8424
VL - 117
SP - 15262
EP - 15269
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 26
ER -