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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)
Inactivating genetic variants in the Unfolded Protein Response (UPR) regulator Activating Transcription Factor 6 (ATF6) result in loss of color vision, which is linked to dysfunctional cone photoreceptors and the development of achromatopsia. The pathomechanims involving the lack of functional ATF6 remain unknown; retinal organoids from patient induced pluripotent stem cells and ATF6 null hESCs were generated to elucidate this question. Data from this study identified an unexpected UPR-independent role for ATF6 signaling during cone photoreceptor differentiation in human retinal development, identifying a pathogenic mechanism underlying ATF6-associated achromatopsia. It is believed that pharmacologic targeting of ATF6 may present a viable treatment option for color blinding diseases at early stages of retinal 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 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.
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.
Competing interest statement: J.W.K. declares that he is a board member and shareholder of Proteostasis Therapeutics Inc., Protego BioPharma, and Yumanity, which may develop ATF6 activators to treat degenerative diseases, although not for stem cell–associated purposes at this time. R.L.W. is a shareholder and board member of Protego BioPharma. J.W.K. and R.L.W. are inventors on a patent describing the ATF6 activating compound used in this study. All other authors declare they have no competing interests.
This article is a PNAS Direct Submission. V.Y.A. is a guest editor invited by the Editorial Board.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2103196118/-/DCSupplemental.
The RNA-seq data have been deposited to the public National Center for Biotechnology Information Gene Expression Omnibus repository under the data identifier GSE153302. All other study data are included in the article and/or supporting information.
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