ATF6 is essential for human cone photoreceptor development. Proc Natl Acad Sci U S A 2021 Sep 28;118(39)
Date
09/26/2021Pubmed ID
34561305Pubmed Central ID
PMC8488632DOI
10.1073/pnas.2103196118Scopus ID
2-s2.0-85117051646 (requires institutional sign-in at Scopus site) 44 CitationsAbstract
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 List
Kroeger H, Grandjean JMD, Chiang WJ, Bindels DD, Mastey R, Okalova J, Nguyen A, Powers ET, Kelly JW, Grimsey NJ, Michaelides M, Carroll J, Wiseman RL, Lin JHAuthor
Joseph J. Carroll PhD Director, Professor in the Ophthalmology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Activating Transcription Factor 6Color Vision Defects
Cone Opsins
Gene Expression
HEK293 Cells
Humans
Induced Pluripotent Stem Cells
Organoids
Retina
Retinal Cone Photoreceptor Cells
Vision, Ocular
