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.
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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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