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Wei-Chieh Jerry Chiang, Xiaoke Bi, Heike Kroeger, Stephanie Landeros, Lingyun Cheng, Jonathan H Lin; Unfolded Protein Response Regulator, ATF6, is Essential for Stress Survival in Cone Photoreceptors. Invest. Ophthalmol. Vis. Sci. 2019;60(9):4206.
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© ARVO (1962-2015); The Authors (2016-present)
The Unfolded Protein Response (UPR) is an essential intracellular signal transduction mechanism that maintains endoplasmic reticulum (ER) homeostasis when the cells are under stress. Mutations in a UPR regulator gene, Activating Transcription Factor 6 (ATF6), were identified as a cause of Achromatopsia (ACHM) and Cone-Rod Dystrophy (CORD), rare heritable retinal dystrophies characterized by severe cone photoreceptor dysfunction, cone photoreceptor degeneration, and for CORD, progressive loss of rod photoreceptor function. To investigate the role of ATF6 in cone photoreceptors, we analyzed retinal phenotypes in an Atf6-deficient and Nrl-/- cone-enriched mouse model.
Cone photoreceptors comprise only 2-3% of total photoreceptor population in the wild-type mouse retina, which makes it challenging to study cone photoreceptor function. Loss of Nrl leads to conversion of rod photoreceptors to S-cone like cells. Nrl-/- mice therefore provide a genetic system to enrich for cone photoreceptors in mice. To study the role of ATF6 in cones, we generated Atf6-/-Nrl-/- mice and analyzed retinal phenotypes by biochemistry, histology, and molecular biology analysis, using mouse eyes and retinal explant culture.
We found that Atf6-/-Nrl-/- cone-enriched explanted retinas were highly sensitive to a wide variety of ER stresses and showed significantly more cone photoreceptor cell death compared to Atf6+/+Nrl-/- retinas at all ages examined (1-month, 3-month, and 12-month old). In addition, Atf6-/- mouse retinas (containing mixed cones and rods) were also more sensitive to ER stress conditions than the control wild-type mouse retinas. However, under basal unstressed conditions, we found that Atf6-/-Nrl-/- mouse retinas have minimal difference in retinal histology and the expression of UPR marker genes, compared to the control mouse retinas.
Our studies show that ATF6 is necessary to protect cone photoreceptors from ER stress and lack of ATF6 increases cone photoreceptor vulnerability to ER stress-induced damage and cell death. Our results suggest that ATF6 mutations cause ACHM and CORD by increasing cone cell vulnerability and cell death in response to physiologic sources of ER stress encountered during retinal development.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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