气候变化领域集成服务门户(CCPortal): ATF6 is essential for human cone photoreceptor development

CCPortal

DOI	10.1073/PNAS.2103196118
	ATF6 is essential for human cone photoreceptor development
	Kroeger H.; Grandjean J.M.D.; Chiang W.-C.J.; Bindels D.D.; Mastey R.; Okalova J.; Nguyen A.; Powers E.T.; Kelly J.W.; Grimsey N.J.; Michaelides M.; Carroll J.; Wiseman R.L.; Lin J.H.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:39
英文摘要	Endoplasmic reticulum (ER) stress and Unfolded Protein Response (UPR) signaling promote the pathology of many human diseases. Loss-of-function variants of the UPR regulator Activating Transcription Factor 6 (ATF6) cause severe congenital vision loss diseases such as achromatopsia by unclear pathomechanisms. To investigate this, we generated retinal organoids from achromatopsia patient induced pluripotent stem cells carrying ATF6 disease variants and from gene-edited ATF6 null hESCs. We found that achromatopsia patient and ATF6 null retinal organoids failed to form cone structures concomitant with loss of cone phototransduction gene expression, while rod photoreceptors developed normally. Adaptive optics retinal imaging of achromatopsia patients carrying ATF6 variants also showed absence of cone inner/outer segment structures but preserved rod structures, mirroring the defect in cone formation observed in our retinal organoids. These results establish that ATF6 is essential for human cone development. Interestingly, we find that a selective small molecule ATF6 signaling agonist restores the transcriptional activity of some ATF6 disease-causing variants and stimulates cone growth and gene expression in patient retinal organoids carrying these variants. These findings support that pharmacologic targeting of the ATF6 pathway can promote human cone development and should be further explored for blinding retinal diseases. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Achromatopsia; ATF6 signaling; Cone photoreceptors; Retinal organoids; Stem cell biology
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/238790
作者单位	Department of Cellular Biology, Franklin College of Arts and Sciences, University of Georgia, Athens, GA 30601, United States; Department of Molecular Medicine, Scripps Research Institute, San Diego, CA 92037, United States; Developmental Neurobiology Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, 904-0495, Japan; Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, CA 92093, United States; Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, WI 53226, United States; College of Pharmacy, Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA 30601, United States; Department of Pathology, Stanford University, Stanford, CA 94305, United States; Department of Chemistry, Scripps Research Institute, San Diego, CA 92037, United States; Skaggs Institute for Chemical Biology, Scripps Research Institute, San Diego, CA 92037, United States; UCL Institute of Ophthalmology, Univers...
推荐引用方式 GB/T 7714	Kroeger H.,Grandjean J.M.D.,Chiang W.-C.J.,et al. ATF6 is essential for human cone photoreceptor development[J],2021,118(39).
APA	Kroeger H..,Grandjean J.M.D..,Chiang W.-C.J..,Bindels D.D..,Mastey R..,...&Lin J.H..(2021).ATF6 is essential for human cone photoreceptor development.Proceedings of the National Academy of Sciences of the United States of America,118(39).
MLA	Kroeger H.,et al."ATF6 is essential for human cone photoreceptor development".Proceedings of the National Academy of Sciences of the United States of America 118.39(2021).