Scleral PERK and ATF6 as targets of myopic axial elongation of mouse eyes

Shin-ichi Ikeda, Toshihide Kurihara (), Xiaoyan Jiang, Yukihiro Miwa, Deokho Lee, Naho Serizawa, Heonuk Jeong, Kiwako Mori, Yusaku Katada, Hiromitsu Kunimi, Nobuhiro Ozawa, Chiho Shoda, Mari Ibuki, Kazuno Negishi, Hidemasa Torii and Kazuo Tsubota ()
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Shin-ichi Ikeda: Keio University School of Medicine
Toshihide Kurihara: Keio University School of Medicine
Xiaoyan Jiang: Keio University School of Medicine
Yukihiro Miwa: Keio University School of Medicine
Deokho Lee: Keio University School of Medicine
Naho Serizawa: Keio University School of Medicine
Heonuk Jeong: Keio University School of Medicine
Kiwako Mori: Keio University School of Medicine
Yusaku Katada: Keio University School of Medicine
Hiromitsu Kunimi: Keio University School of Medicine
Nobuhiro Ozawa: Keio University School of Medicine
Chiho Shoda: Keio University School of Medicine
Mari Ibuki: Keio University School of Medicine
Kazuno Negishi: Keio University School of Medicine
Hidemasa Torii: Keio University School of Medicine
Kazuo Tsubota: Keio University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Axial length is the primary determinant of eye size, and it is elongated in myopia. However, the underlying mechanism of the onset and progression of axial elongation remain unclear. Here, we show that endoplasmic reticulum (ER) stress in sclera is an essential regulator of axial elongation in myopia development through activation of both PERK and ATF6 axis followed by scleral collagen remodeling. Mice with lens-induced myopia (LIM) showed ER stress in sclera. Pharmacological interventions for ER stress could induce or inhibit myopia progression. LIM activated all IRE1, PERK and ATF6 axis, and pharmacological inhibition of both PERK and ATF6 suppressed myopia progression, which was confirmed by knocking down above two genes via CRISPR/Cas9 system. LIM dramatically changed the expression of scleral collagen genes responsible for ER stress. Furthermore, collagen fiber thinning and expression of dysregulated collagens in LIM were ameliorated by 4-PBA administration. We demonstrate that scleral ER stress and PERK/ATF6 pathway controls axial elongation during the myopia development in vivo model and 4-PBA eye drop is promising drug for myopia suppression/treatment.

Date: 2022
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DOI: 10.1038/s41467-022-33605-1

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