Chronic Dicer1 deficiency promotes atrophic and neovascular outer retinal pathologies in mice

Charles B. Wright; Hironori Uehara; Younghee Kim; Tetsuhiro Yasuma; Reo Yasuma; Shuichiro Hirahara; Ryan D. Makin; Ivana Apicella; Felipe Pereira; Yosuke Nagasaka; Siddharth Narendran; Shinichi Fukuda; Romulo Albuquerque; Benjamin J. Fowler; Ana Bastos-Carvalho; Philippe Georgel; Izuho Hatada; Bo Chang; Nagaraj Kerur; Balamurali K. Ambati; Jayakrishna Ambati; Bradley D. Gelfand

doi:10.1073/pnas.1909761117

Chronic Dicer1 deficiency promotes atrophic and neovascular outer retinal pathologies in mice

Charles B. Wright, Hironori Uehara, Younghee Kim, Tetsuhiro Yasuma, Reo Yasuma, Shuichiro Hirahara, Ryan D. Makin, Ivana Apicella, Felipe Pereira, Yosuke Nagasaka, Siddharth Narendran, Shinichi Fukuda, Romulo Albuquerque, Benjamin J. Fowler, Ana Bastos-Carvalho, Philippe Georgel, Izuho Hatada, Bo Chang, Nagaraj Kerur, Balamurali K. AmbatiJayakrishna Ambati, Bradley D. Gelfand

Opthalmology

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	2579-2587
Number of pages	9
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	117
Issue number	5
DOIs	https://doi.org/10.1073/pnas.1909761117
State	Published - Feb 4 2020

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. We thank G. Pattison, K. Langberg, D. Robertson, X. Zhou, K. Atwood, and H. Hall for their technical assistance. These studies were supported by NIH Grant R01EY028027 and American Heart Association Grant 13SDG16770008 (B.D.G.); J.A. was supported by NIH Grants DP1GM114862, R01EY022238, R01EY024068, R01EY028027, and R01EY029799; John Templeton Foundation Grant 60763; and the DuPont Guerry, III, Professorship; N.K. by NIH Grants K99EY024336 and R00EY024336; R.D.M. by NIH Grant T32 HL007284; B.K.A. and H.U. by NIH Grants R01EY017950 and R01EY017182; and B.C. by NIH Grant R01EY019943. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.

Keywords

Choroidal neovascularization
Dicer
Inflammasome
Retina

ASJC Scopus subject areas

General

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10.1073/pnas.1909761117

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Wright, C. B., Uehara, H., Kim, Y., Yasuma, T., Yasuma, R., Hirahara, S., Makin, R. D., Apicella, I., Pereira, F., Nagasaka, Y., Narendran, S., Fukuda, S., Albuquerque, R., Fowler, B. J., Bastos-Carvalho, A., Georgel, P., Hatada, I., Chang, B., Kerur, N., ... Gelfand, B. D. (2020). Chronic Dicer1 deficiency promotes atrophic and neovascular outer retinal pathologies in mice. Proceedings of the National Academy of Sciences of the United States of America, 117(5), 2579-2587. https://doi.org/10.1073/pnas.1909761117

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title = "Chronic Dicer1 deficiency promotes atrophic and neovascular outer retinal pathologies in mice",

abstract = "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.",

keywords = "Choroidal neovascularization, Dicer, Inflammasome, Retina",

author = "Wright, {Charles B.} and Hironori Uehara and Younghee Kim and Tetsuhiro Yasuma and Reo Yasuma and Shuichiro Hirahara and Makin, {Ryan D.} and Ivana Apicella and Felipe Pereira and Yosuke Nagasaka and Siddharth Narendran and Shinichi Fukuda and Romulo Albuquerque and Fowler, {Benjamin J.} and Ana Bastos-Carvalho and Philippe Georgel and Izuho Hatada and Bo Chang and Nagaraj Kerur and Ambati, {Balamurali K.} and Jayakrishna Ambati and Gelfand, {Bradley D.}",

note = "Funding Information: ACKNOWLEDGMENTS. We thank G. Pattison, K. Langberg, D. Robertson, X. Zhou, K. Atwood, and H. Hall for their technical assistance. These studies were supported by NIH Grant R01EY028027 and American Heart Association Grant 13SDG16770008 (B.D.G.); J.A. was supported by NIH Grants DP1GM114862, R01EY022238, R01EY024068, R01EY028027, and R01EY029799; John Templeton Foundation Grant 60763; and the DuPont Guerry, III, Professorship; N.K. by NIH Grants K99EY024336 and R00EY024336; R.D.M. by NIH Grant T32 HL007284; B.K.A. and H.U. by NIH Grants R01EY017950 and R01EY017182; and B.C. by NIH Grant R01EY019943. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Publisher Copyright: {\textcopyright} 2020 National Academy of Sciences. All rights reserved.",

year = "2020",

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doi = "10.1073/pnas.1909761117",

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Wright, CB, Uehara, H, Kim, Y, Yasuma, T, Yasuma, R, Hirahara, S, Makin, RD, Apicella, I, Pereira, F, Nagasaka, Y, Narendran, S, Fukuda, S, Albuquerque, R, Fowler, BJ, Bastos-Carvalho, A, Georgel, P, Hatada, I, Chang, B, Kerur, N, Ambati, BK, Ambati, J & Gelfand, BD 2020, 'Chronic Dicer1 deficiency promotes atrophic and neovascular outer retinal pathologies in mice', Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 5, pp. 2579-2587. https://doi.org/10.1073/pnas.1909761117

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 - Funding Information: ACKNOWLEDGMENTS. We thank G. Pattison, K. Langberg, D. Robertson, X. Zhou, K. Atwood, and H. Hall for their technical assistance. These studies were supported by NIH Grant R01EY028027 and American Heart Association Grant 13SDG16770008 (B.D.G.); J.A. was supported by NIH Grants DP1GM114862, R01EY022238, R01EY024068, R01EY028027, and R01EY029799; John Templeton Foundation Grant 60763; and the DuPont Guerry, III, Professorship; N.K. by NIH Grants K99EY024336 and R00EY024336; R.D.M. by NIH Grant T32 HL007284; B.K.A. and H.U. by NIH Grants R01EY017950 and R01EY017182; and B.C. by NIH Grant R01EY019943. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. 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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Chronic Dicer1 deficiency promotes atrophic and neovascular outer retinal pathologies in mice

Abstract

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Keywords

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