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ATF6 is essential for human cone photoreceptor development

Kroeger, H; Grandjean, JMD; Chiang, W-CJ; Bindels, DD; Mastey, R; Okalova, J; Nguyen, A; ... Lin, JH; + view all (2021) ATF6 is essential for human cone photoreceptor development. Proceedings of the National Academy of Sciences (PNAS) , 118 (39) , Article e2103196118. 10.1073/pnas.2103196118. Green open access

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Abstract

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.

Type: Article
Title: ATF6 is essential for human cone photoreceptor development
Open access status: An open access version is available from UCL Discovery
DOI: 10.1073/pnas.2103196118
Publisher version: https://doi.org/10.1073/pnas.2103196118
Language: English
Additional information: This version is the version of record. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Cone photoreceptors, retinal organoids, ATF6 signaling, achromatopsia, stem cell biology
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10137612
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