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 results establish that ATF6 is essential for human cone development.
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. 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. 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.
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. 14 Veterans Affairs Palo Alto Healthcare System, Palo Alto, CA 94304.Įndoplasmic reticulum (ER) stress and Unfolded Protein Response (UPR) signaling promote the pathology of many human diseases.12 Department of Pathology, Stanford University, Stanford, CA 94305 13 Department of Ophthalmology, Stanford University, Palo Alto, CA 94303.11 Moorfields Eye Hospital, London EC1V 2PD, United Kingdom.10 UCL Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom.9 Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, CA 92037.8 Department of Chemistry, Scripps Research Institute, La Jolla, CA 92037.7 Department of Pathology, Stanford University, Stanford, CA 94305.6 College of Pharmacy, Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA 30601.5 Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, WI 53226.4 Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093.3 Developmental Neurobiology Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa 904-0495, Japan.1 Department of Cellular Biology, Franklin College of Arts and Sciences, University of Georgia, Athens, GA 30601 2 Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA 92037.
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