ATF6 is essential for human cone photoreceptor development

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 pathomec...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 39; pp. 1 - 9
Main Authors:	Kroeger, Heike, Grandjean, Julia M. D., Chiang, Wei-Chieh Jerry, Bindels, Daphne D., Mastey, Rebecca, Okalova, Jennifer, Nguyen, Amanda, Powers, Evan T., Kelly, Jeffery W., Grimsey, Neil J., Michaelides, Michel, Carroll, Joseph, Wiseman, R. Luke, Lin, Jonathan H.
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 28-09-2021
Subjects:	Activating transcription factor 6 Activating Transcription Factor 6 - agonists Activating Transcription Factor 6 - genetics Activating Transcription Factor 6 - metabolism Adaptive optics Biological Sciences Color blindness Color Vision Defects - genetics Cone Opsins - genetics Diseases Endoplasmic reticulum Gene Expression Genetic modification HEK293 Cells Humans Induced Pluripotent Stem Cells - cytology Optics Organoids Photoreceptors Phototransduction Pluripotency Protein folding Retina Retina - cytology Retina - diagnostic imaging Retinal Cone Photoreceptor Cells - pathology Retinal Cone Photoreceptor Cells - physiology Retinal images Rod outer segment membranes Signaling Stem cells Vision, Ocular - genetics ATF6 signaling cone photoreceptors achromatopsia retinal organoids stem cell biology
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-3 content type line 23 ObjectType-Undefined-2 Edited by Vadim Y. Arshavsky, Duke University School of Medicine, Durham, NC, and accepted by Editorial Board Member Jeremy Nathans August 3, 2021 (received for review February 17, 2021) Author contributions: H.K. and J.H.L. designed research; H.K., W.-C.J.C., R.M., J.O., A.N., and N.J.G. performed research; H.K., J.M.D.G., W.-C.J.C., D.D.B., R.M., E.T.P., J.W.K., N.J.G., M.M., J.C., R.L.W., and J.H.L. analyzed data; and H.K., R.L.W., and J.H.L. wrote the paper.
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.2103196118