Development of a Pde6b gene knockout rat model for studies of degenerative retinal diseases

Joon Hyung Yeo; Bok Kyoung Jung; Heuiran Lee; In Jeoung Baek; Young Hoon Sung; Hae Sol Shin; Hong Kyung Kim; Kyoung Yul Seo; Joo Yong Lee

doi:10.1167/iovs.18-25556

Development of a Pde6b gene knockout rat model for studies of degenerative retinal diseases

Joon Hyung Yeo, Bok Kyoung Jung, Heuiran Lee, In Jeoung Baek, Young Hoon Sung, Hae Sol Shin, Hong Kyung Kim, Kyoung Yul Seo, Joo Yong Lee

Department of Ophthalmology

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6 Citations (Scopus)

Abstract

PURPOSE. To describe the phenotypes of a newly developed Pde6b-deficient rat model of retinal degeneration. METHODS. Pde6b knockout rats were produced by CRISPR-Cpf1 technology. Pde6b knockout rats were evaluated for ocular abnormalities by comparison with wild-type eyes. Eyes were imaged using fundus photography and optical coherence tomography (OCT), stained by hematoxylin and eosin (H&E), and examined by TUNEL assay. Finally, eyes were functionally assessed by electroretinograms (ERGs). RESULTS. Pde6b knockout rats exhibited visible photoreceptor degeneration at 3 weeks of postnatal age. The fundus appearance of mutants was notable for pigmentary changes, vascular attenuation with an irregular vascular pattern, and outer retinal thinning, which resembled retinitis pigmentosa (RP) in humans. OCT showed profound retinal thinning in Pde6b knockout rats; the outer nuclear layer (ONL) was significantly thinner in Pde6b knockout rats, with relative preservation of the inner retina at 3 weeks of postnatal age. H&E staining confirmed extensive degeneration of the ONL, beginning at 3 weeks of postnatal age; no ONL remained in the retina by 16 weeks of postnatal age. Retinal sections of Pde6b knockout rats were highly positive for TUNEL, specifically in the ONL. In ERGs, Pde6b knockout rats showed no detectable a-or b-waves at 8 weeks of postnatal age. CONCLUSIONS. The Pde6b knockout rat exhibits photoreceptor degeneration. It may provide a better model for experimental therapy for RP because of its slower progression and larger anatomic architecture than the corresponding mouse model. Further studies in this rat model may yield insights into effective therapies for human RP.

Original language	English
Pages (from-to)	1519-1526
Number of pages	8
Journal	Investigative Ophthalmology and Visual Science
Volume	60
Issue number	5
DOIs	https://doi.org/10.1167/iovs.18-25556
Publication status	Published - 2019 Apr

Bibliographical note

Funding Information:
Supported by grants from the Ministry of Health & Welfare (HI15C2599, 2016; JYL), and Korea Mouse Phenotyping Project (NRF-2013M3A9D5072551; KYS) of the Ministry of Science and ICT through the National Research Foundation and Asan Institute for Life Sciences (2018-484; JYL), Asan Medical Center, Seoul, Republic of Korea. Disclosure: J.H. Yeo, None; B.K. Jung, None; H. Lee, None; I.-J. Baek, None; Y.H. Sung, None; H.-S. Shin, None; H.-K. Kim, None; K.Y. Seo, None; J.Y. Lee, None

Funding Information:
The authors thank the core facilities of Genetically Engineered Animal Research (GEAR) and Mammalian Genetics (MG) at the ConveRgence mEDIcine research center (CREDIT), Asan Medical Center, for the use of their shared equipment, services, and expertise. Supported by grants from the Ministry of Health & Welfare (HI15C2599, 2016; JYL), and Korea Mouse Phenotyping Project (NRF-2013M3A9D5072551; KYS) of the Ministry of Science and ICT through the National Research Foundation and Asan Institute for Life Sciences (2018-484; JYL), Asan Medical Center, Seoul, Republic of Korea.

Publisher Copyright:
© 2019 The Authors.

All Science Journal Classification (ASJC) codes

Ophthalmology
Sensory Systems
Cellular and Molecular Neuroscience

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10.1167/iovs.18-25556

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@article{d61a971b6ba44acf998d8e3d1514f28f,

title = "Development of a Pde6b gene knockout rat model for studies of degenerative retinal diseases",

abstract = "PURPOSE. To describe the phenotypes of a newly developed Pde6b-deficient rat model of retinal degeneration. METHODS. Pde6b knockout rats were produced by CRISPR-Cpf1 technology. Pde6b knockout rats were evaluated for ocular abnormalities by comparison with wild-type eyes. Eyes were imaged using fundus photography and optical coherence tomography (OCT), stained by hematoxylin and eosin (H&E), and examined by TUNEL assay. Finally, eyes were functionally assessed by electroretinograms (ERGs). RESULTS. Pde6b knockout rats exhibited visible photoreceptor degeneration at 3 weeks of postnatal age. The fundus appearance of mutants was notable for pigmentary changes, vascular attenuation with an irregular vascular pattern, and outer retinal thinning, which resembled retinitis pigmentosa (RP) in humans. OCT showed profound retinal thinning in Pde6b knockout rats; the outer nuclear layer (ONL) was significantly thinner in Pde6b knockout rats, with relative preservation of the inner retina at 3 weeks of postnatal age. H&E staining confirmed extensive degeneration of the ONL, beginning at 3 weeks of postnatal age; no ONL remained in the retina by 16 weeks of postnatal age. Retinal sections of Pde6b knockout rats were highly positive for TUNEL, specifically in the ONL. In ERGs, Pde6b knockout rats showed no detectable a-or b-waves at 8 weeks of postnatal age. CONCLUSIONS. The Pde6b knockout rat exhibits photoreceptor degeneration. It may provide a better model for experimental therapy for RP because of its slower progression and larger anatomic architecture than the corresponding mouse model. Further studies in this rat model may yield insights into effective therapies for human RP.",

author = "Yeo, {Joon Hyung} and Jung, {Bok Kyoung} and Heuiran Lee and Baek, {In Jeoung} and Sung, {Young Hoon} and Shin, {Hae Sol} and Kim, {Hong Kyung} and Seo, {Kyoung Yul} and Lee, {Joo Yong}",

note = "Funding Information: Supported by grants from the Ministry of Health & Welfare (HI15C2599, 2016; JYL), and Korea Mouse Phenotyping Project (NRF-2013M3A9D5072551; KYS) of the Ministry of Science and ICT through the National Research Foundation and Asan Institute for Life Sciences (2018-484; JYL), Asan Medical Center, Seoul, Republic of Korea. Disclosure: J.H. Yeo, None; B.K. Jung, None; H. Lee, None; I.-J. Baek, None; Y.H. Sung, None; H.-S. Shin, None; H.-K. Kim, None; K.Y. Seo, None; J.Y. Lee, None Funding Information: The authors thank the core facilities of Genetically Engineered Animal Research (GEAR) and Mammalian Genetics (MG) at the ConveRgence mEDIcine research center (CREDIT), Asan Medical Center, for the use of their shared equipment, services, and expertise. Supported by grants from the Ministry of Health & Welfare (HI15C2599, 2016; JYL), and Korea Mouse Phenotyping Project (NRF-2013M3A9D5072551; KYS) of the Ministry of Science and ICT through the National Research Foundation and Asan Institute for Life Sciences (2018-484; JYL), Asan Medical Center, Seoul, Republic of Korea. Publisher Copyright: {\textcopyright} 2019 The Authors.",

year = "2019",

month = apr,

doi = "10.1167/iovs.18-25556",

language = "English",

volume = "60",

pages = "1519--1526",

journal = "Investigative Ophthalmology",

issn = "0146-0404",

publisher = "Association for Research in Vision and Ophthalmology Inc.",

number = "5",

}

Development of a Pde6b gene knockout rat model for studies of degenerative retinal diseases. / Yeo, Joon Hyung; Jung, Bok Kyoung; Lee, Heuiran; Baek, In Jeoung; Sung, Young Hoon; Shin, Hae Sol; Kim, Hong Kyung; Seo, Kyoung Yul; Lee, Joo Yong.

In: Investigative Ophthalmology and Visual Science, Vol. 60, No. 5, 04.2019, p. 1519-1526.

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

TY - JOUR

T1 - Development of a Pde6b gene knockout rat model for studies of degenerative retinal diseases

AU - Yeo, Joon Hyung

AU - Jung, Bok Kyoung

AU - Lee, Heuiran

AU - Baek, In Jeoung

AU - Sung, Young Hoon

AU - Shin, Hae Sol

AU - Kim, Hong Kyung

AU - Seo, Kyoung Yul

AU - Lee, Joo Yong

N1 - Funding Information: Supported by grants from the Ministry of Health & Welfare (HI15C2599, 2016; JYL), and Korea Mouse Phenotyping Project (NRF-2013M3A9D5072551; KYS) of the Ministry of Science and ICT through the National Research Foundation and Asan Institute for Life Sciences (2018-484; JYL), Asan Medical Center, Seoul, Republic of Korea. Disclosure: J.H. Yeo, None; B.K. Jung, None; H. Lee, None; I.-J. Baek, None; Y.H. Sung, None; H.-S. Shin, None; H.-K. Kim, None; K.Y. Seo, None; J.Y. Lee, None Funding Information: The authors thank the core facilities of Genetically Engineered Animal Research (GEAR) and Mammalian Genetics (MG) at the ConveRgence mEDIcine research center (CREDIT), Asan Medical Center, for the use of their shared equipment, services, and expertise. Supported by grants from the Ministry of Health & Welfare (HI15C2599, 2016; JYL), and Korea Mouse Phenotyping Project (NRF-2013M3A9D5072551; KYS) of the Ministry of Science and ICT through the National Research Foundation and Asan Institute for Life Sciences (2018-484; JYL), Asan Medical Center, Seoul, Republic of Korea. Publisher Copyright: © 2019 The Authors.

PY - 2019/4

Y1 - 2019/4

N2 - PURPOSE. To describe the phenotypes of a newly developed Pde6b-deficient rat model of retinal degeneration. METHODS. Pde6b knockout rats were produced by CRISPR-Cpf1 technology. Pde6b knockout rats were evaluated for ocular abnormalities by comparison with wild-type eyes. Eyes were imaged using fundus photography and optical coherence tomography (OCT), stained by hematoxylin and eosin (H&E), and examined by TUNEL assay. Finally, eyes were functionally assessed by electroretinograms (ERGs). RESULTS. Pde6b knockout rats exhibited visible photoreceptor degeneration at 3 weeks of postnatal age. The fundus appearance of mutants was notable for pigmentary changes, vascular attenuation with an irregular vascular pattern, and outer retinal thinning, which resembled retinitis pigmentosa (RP) in humans. OCT showed profound retinal thinning in Pde6b knockout rats; the outer nuclear layer (ONL) was significantly thinner in Pde6b knockout rats, with relative preservation of the inner retina at 3 weeks of postnatal age. H&E staining confirmed extensive degeneration of the ONL, beginning at 3 weeks of postnatal age; no ONL remained in the retina by 16 weeks of postnatal age. Retinal sections of Pde6b knockout rats were highly positive for TUNEL, specifically in the ONL. In ERGs, Pde6b knockout rats showed no detectable a-or b-waves at 8 weeks of postnatal age. CONCLUSIONS. The Pde6b knockout rat exhibits photoreceptor degeneration. It may provide a better model for experimental therapy for RP because of its slower progression and larger anatomic architecture than the corresponding mouse model. Further studies in this rat model may yield insights into effective therapies for human RP.

AB - PURPOSE. To describe the phenotypes of a newly developed Pde6b-deficient rat model of retinal degeneration. METHODS. Pde6b knockout rats were produced by CRISPR-Cpf1 technology. Pde6b knockout rats were evaluated for ocular abnormalities by comparison with wild-type eyes. Eyes were imaged using fundus photography and optical coherence tomography (OCT), stained by hematoxylin and eosin (H&E), and examined by TUNEL assay. Finally, eyes were functionally assessed by electroretinograms (ERGs). RESULTS. Pde6b knockout rats exhibited visible photoreceptor degeneration at 3 weeks of postnatal age. The fundus appearance of mutants was notable for pigmentary changes, vascular attenuation with an irregular vascular pattern, and outer retinal thinning, which resembled retinitis pigmentosa (RP) in humans. OCT showed profound retinal thinning in Pde6b knockout rats; the outer nuclear layer (ONL) was significantly thinner in Pde6b knockout rats, with relative preservation of the inner retina at 3 weeks of postnatal age. H&E staining confirmed extensive degeneration of the ONL, beginning at 3 weeks of postnatal age; no ONL remained in the retina by 16 weeks of postnatal age. Retinal sections of Pde6b knockout rats were highly positive for TUNEL, specifically in the ONL. In ERGs, Pde6b knockout rats showed no detectable a-or b-waves at 8 weeks of postnatal age. CONCLUSIONS. The Pde6b knockout rat exhibits photoreceptor degeneration. It may provide a better model for experimental therapy for RP because of its slower progression and larger anatomic architecture than the corresponding mouse model. Further studies in this rat model may yield insights into effective therapies for human RP.

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DO - 10.1167/iovs.18-25556

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JO - Investigative Ophthalmology

JF - Investigative Ophthalmology

SN - 0146-0404

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Development of a Pde6b gene knockout rat model for studies of degenerative retinal diseases

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