TY - JOUR
T1 - Chronic Dicer1 deficiency promotes atrophic and neovascular outer retinal pathologies in mice
AU - Wright, Charles B.
AU - Uehara, Hironori
AU - Kim, Younghee
AU - Yasuma, Tetsuhiro
AU - Yasuma, Reo
AU - Hirahara, Shuichiro
AU - Makin, Ryan D.
AU - Apicella, Ivana
AU - Pereira, Felipe
AU - Nagasaka, Yosuke
AU - Narendran, Siddharth
AU - Fukuda, Shinichi
AU - Albuquerque, Romulo
AU - Fowler, Benjamin J.
AU - Bastos-Carvalho, Ana
AU - Georgel, Philippe
AU - Hatada, Izuho
AU - Chang, Bo
AU - Kerur, Nagaraj
AU - Ambati, Balamurali K.
AU - Ambati, Jayakrishna
AU - Gelfand, Bradley D.
N1 - Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/2/4
Y1 - 2020/2/4
N2 - Degeneration of the retinal pigmented epithelium (RPE) and aberrant blood vessel growth in the eye are advanced-stage processes in blinding diseases such as age-related macular degeneration (AMD), which affect hundreds of millions of people worldwide. Loss of the RNase DICER1, an essential factor in micro-RNA biogenesis, is implicated in RPE atrophy. However, the functional implications of DICER1 loss in choroidal and retinal neovascularization are unknown. Here, we report that two independent hypomorphic mouse strains, as well as a separate model of postnatal RPE-specific DICER1 ablation, all presented with spontaneous RPE degeneration and choroidal and retinal neovascularization. DICER1 hypomorphic mice lacking critical inflammasome components or the innate immune adaptor MyD88 developed less severe RPE atrophy and pathological neovascularization. DICER1 abundance was also reduced in retinas of the JR5558 mouse model of spontaneous choroidal neovascularization. Finally, adenoassociated vector-mediated gene delivery of a truncated DICER1 variant (OptiDicer) reduced spontaneous choroidal neovascularization in JR5558 mice. Collectively, these findings significantly expand the repertoire of DICER1 in preserving retinal homeostasis by preventing both RPE degeneration and pathological neovascularization.
AB - Degeneration of the retinal pigmented epithelium (RPE) and aberrant blood vessel growth in the eye are advanced-stage processes in blinding diseases such as age-related macular degeneration (AMD), which affect hundreds of millions of people worldwide. Loss of the RNase DICER1, an essential factor in micro-RNA biogenesis, is implicated in RPE atrophy. However, the functional implications of DICER1 loss in choroidal and retinal neovascularization are unknown. Here, we report that two independent hypomorphic mouse strains, as well as a separate model of postnatal RPE-specific DICER1 ablation, all presented with spontaneous RPE degeneration and choroidal and retinal neovascularization. DICER1 hypomorphic mice lacking critical inflammasome components or the innate immune adaptor MyD88 developed less severe RPE atrophy and pathological neovascularization. DICER1 abundance was also reduced in retinas of the JR5558 mouse model of spontaneous choroidal neovascularization. Finally, adenoassociated vector-mediated gene delivery of a truncated DICER1 variant (OptiDicer) reduced spontaneous choroidal neovascularization in JR5558 mice. Collectively, these findings significantly expand the repertoire of DICER1 in preserving retinal homeostasis by preventing both RPE degeneration and pathological neovascularization.
KW - Choroidal neovascularization
KW - Dicer
KW - Inflammasome
KW - Retina
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U2 - 10.1073/pnas.1909761117
DO - 10.1073/pnas.1909761117
M3 - Article
C2 - 31964819
AN - SCOPUS:85079019612
SN - 0027-8424
VL - 117
SP - 2579
EP - 2587
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 5
ER -