TY - JOUR
T1 - Scleral PERK and ATF6 as targets of myopic axial elongation of mouse eyes
AU - Ikeda, Shin ichi
AU - Kurihara, Toshihide
AU - Jiang, Xiaoyan
AU - Miwa, Yukihiro
AU - Lee, Deokho
AU - Serizawa, Naho
AU - Jeong, Heonuk
AU - Mori, Kiwako
AU - Katada, Yusaku
AU - Kunimi, Hiromitsu
AU - Ozawa, Nobuhiro
AU - Shoda, Chiho
AU - Ibuki, Mari
AU - Negishi, Kazuno
AU - Torii, Hidemasa
AU - Tsubota, Kazuo
N1 - Funding Information:
We thank K Mori, T Ishikawa, and T Okada (Department of Biophysics, Graduate School of Science, Kyoto University) for meaningful discussions and suggestions, and T Nagai (Laboratory of Electron Microscopy, Keio University School of Medicine) for support with TEM observation, and Y Sato and K Nagashima (Clinical and Translational Research Center, Keio University Hospital) for support with Statistical analysis, and K Kurosaki and A Kawabata for their excellent technical assistance. We are also grateful to the Collaborative Research Resources, School of Medicine, Keio University, for technical support and reagents. This work was supported by grants (S. I.) from KAKENHI (Grant-in-Aid for Scientific Research (B): 16H03258 and Grant-in-Aid for Scientific Research (C): 20K09834) from the Ministry of Education, Culture, Sports, Science and Technology of Japan and AMO Japan’s Contracted Research Grant (AS2020A000130617). This work was also supported by a grant for myopia research from Tsubota Laboratory, Inc. (Tokyo Japan).
Funding Information:
We thank K Mori, T Ishikawa, and T Okada (Department of Biophysics, Graduate School of Science, Kyoto University) for meaningful discussions and suggestions, and T Nagai (Laboratory of Electron Microscopy, Keio University School of Medicine) for support with TEM observation, and Y Sato and K Nagashima (Clinical and Translational Research Center, Keio University Hospital) for support with Statistical analysis, and K Kurosaki and A Kawabata for their excellent technical assistance. We are also grateful to the Collaborative Research Resources, School of Medicine, Keio University, for technical support and reagents. This work was supported by grants (S. I.) from KAKENHI (Grant-in-Aid for Scientific Research (B): 16H03258 and Grant-in-Aid for Scientific Research (C): 20K09834) from the Ministry of Education, Culture, Sports, Science and Technology of Japan and AMO Japan’s Contracted Research Grant (AS2020A000130617). This work was also supported by a grant for myopia research from Tsubota Laboratory, Inc. (Tokyo Japan).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-022-33605-1
DO - 10.1038/s41467-022-33605-1
M3 - Article
C2 - 36216837
AN - SCOPUS:85139483479
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5859
ER -