Abstract
Purpose :
Activating transcription factor 6 (ATF6) is required for endoplasmic reticulum (ER) function and protein homeostasis and is a key regulator of the unfolded protein response (UPR). Patients carrying loss-of-function ATF6 disease alleles develop the cone dysfunction disorder achromatopsia (ACHM). To investigate the role of ATF6 in cone photoreceptors, we analyzed retinal phenotypes in an Atf6-/-Nrl-/- (neural retina leucine zipper, cone-enriched) mouse model under normal and experimental ER stress.
Methods :
The Nrl-/- mouse develops an S-cone-dominant retina and is a powerful genetic model to study cones because wild-type (WT) mice retinas only have a 3% cone photoreceptor population. We generated Atf6-/-Nrl-/- mice to study ATF6's role in cones and analyzed their 3-month-old retinal phenotypes using biochemical, histological, and molecular biology methods. The analyses were conducted on mouse eyes and retinal explants. We also challenged retinal explants to 2 forms of ER stress: Tunicamycin (1μg/μL) and hypoxia (1% O2).
Results :
Atf6-/-Nrl-/- mice developed S-cone-dominant retinas indistinguishable from Nrl-/- mice under normal vivarium conditions. However, when challenged with ER stress (either Tunicamycin or hypoxia), significantly more cell death was seen in Atf6-/-Nrl-/- mice. This corresponded with defects in ER proteostasis genes. We also identified defects in HIF-1α after hypoxia in the absence of ATF6.
Conclusions :
We conclude that ATF6 is important to protect cone-dominant Nrl-/- retina from ER stress. However, ATF6 is not needed for cone development in mice. Based on these findings, we speculate that human cones encounter a unique ER stress during development not encountered by mice. This may explain why patients lacking ATF6 function develop cone dysfunction and achromatopsia.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.