The Unfolded Protein Response Regulator, ATF6, is Essential for Cone Photoreceptor Development
The Unfolded Protein Response is a conserved intracellular signal transduction mechanism that maintains endoplasmic reticulum homeostasis and may contribute to the pathogenesis and progression of human diseases associated with ER stress.  Genetic mutations in the UPR regulator, ATF6, lead to vision loss in heritable retinal diseases.  Our prior studies found that disease mutations disrupt ATF6 function, but the pathomechanism by which loss of ATF6 activity causes vision loss in people is unknown.  To investigate this, we developed retinal organoids from patient iPSCs carrying ATF6 disease mutations and from hESCs bearing CRISPR-edited ATF6 null alleles.  Unexpectedly, we found that retinal organoids lacking functional ATF6 failed to form cone photoreceptors while rod photoreceptors were unaffected.  We used adaptive optics imaging of the retinas in patients with ATF6 mutations and saw pronounced loss of cones and preservation of rods that closely mirrored our in vitro organoid phenotypes.  Last, we found that a small molecule proteostasis agonist partially restored cone photoreceptor outer segment formation and gene expression in ATF6 mutant retinal organoids.  Our results reveal a surprising and novel function for ATF6 in human cone photoreceptor development.  Our findings identify a potential therapeutic strategy for patients based on small molecule reprogramming of the proteostasis network in the retina.  Our study suggests that the UPR guides intrinsic developmental processes in specialized metazoan cell types in addition to its role in responding to extrinsic pathologic events. Overall design: Comparisons of the transcriptomes of retinal organoids harboring either the homozygous or heterozygous ATF6 Y567N mutation and treatment with ATF6 activator 147.