Journal Article

ATF6 is essential for human cone photoreceptor development

Kroeger, Heike, Mastey, Rebecca, Grandjean, Julia M. D., Bindels, Daphne D., Powers, Evan T., Chiang, Wei-Chieh Jerry, Okalova, Jennifer, Grimsey, Neil J., Carroll, Joseph, Wiseman, R. Luke, Nguyen, Amanda, Lin, Jonathan H., Kelly, Jeffery W., Michaelides, Michel

2021

نظرة عامة

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.

• الناشر: National Academy of Sciences
• موضوع: Activating transcription factor 6 / Activating Transcription Factor 6 - agonists / Activating Transcription Factor 6 - genetics / Activating Transcription Factor 6 - metabolism / Adaptive optics / Biological Sciences / Cell Biology / Color blindness / Color Vision Defects - genetics / Cone Opsins - genetics / 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