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Mettl14-mediated m6A modification is essential for visual function and retinal photoreceptor survival

BACKGROUND: As the most abundant epigenetic modification of eukaryotic mRNA, N6-methyladenosine (m6A) modification has been shown to play a role in mammalian nervous system development and function by regulating mRNA synthesis and degeneration. However, the role of m6A modification in retinal photor...

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Autores principales: Yang, Yeming, Shuai, Ping, Li, Xiao, Sun, Kuanxiang, Jiang, Xiaoyan, Liu, Wenjing, Le, Weidong, Jiang, Haisong, Liu, Yuping, Zhu, Xianjun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9195452/
https://www.ncbi.nlm.nih.gov/pubmed/35698136
http://dx.doi.org/10.1186/s12915-022-01335-x
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author Yang, Yeming
Shuai, Ping
Li, Xiao
Sun, Kuanxiang
Jiang, Xiaoyan
Liu, Wenjing
Le, Weidong
Jiang, Haisong
Liu, Yuping
Zhu, Xianjun
author_facet Yang, Yeming
Shuai, Ping
Li, Xiao
Sun, Kuanxiang
Jiang, Xiaoyan
Liu, Wenjing
Le, Weidong
Jiang, Haisong
Liu, Yuping
Zhu, Xianjun
author_sort Yang, Yeming
collection PubMed
description BACKGROUND: As the most abundant epigenetic modification of eukaryotic mRNA, N6-methyladenosine (m6A) modification has been shown to play a role in mammalian nervous system development and function by regulating mRNA synthesis and degeneration. However, the role of m6A modification in retinal photoreceptors remains unknown. RESULTS: We generated the first retina-specific Mettl14-knockout mouse models using the Rho-Cre and HRGP-Cre lines and investigated the functions of Mettl14 in retinal rod and cone photoreceptors. Our data showed that loss of Mettl14 in rod cells causes a weakened scotopic photoresponse and rod degeneration. Further study revealed the ectopic accumulation of multiple outer segment (OS) proteins in the inner segment (IS). Deficiency of Mettl14 in cone cells led to the mislocalization of cone opsin proteins and the progressive death of cone cells. Moreover, Mettl14 depletion resulted in drastic decreases in METTL3/WTAP levels and reduced m6A methylation levels. Mechanistically, transcriptomic analyses in combination with MeRIP-seq illustrated that m6A depletion via inactivation of Mettl14 resulted in reduced expression levels of multiple phototransduction- and cilium-associated genes, which subsequently led to compromised ciliogenesis and impaired synthesis and transport of OS-residing proteins in rod cells. CONCLUSIONS: Our data demonstrate that Mettl14 plays an important role in regulating phototransduction and ciliogenesis events and is essential for photoreceptor function and survival, highlighting the importance of m6A modification in visual function. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12915-022-01335-x.
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spelling pubmed-91954522022-06-15 Mettl14-mediated m6A modification is essential for visual function and retinal photoreceptor survival Yang, Yeming Shuai, Ping Li, Xiao Sun, Kuanxiang Jiang, Xiaoyan Liu, Wenjing Le, Weidong Jiang, Haisong Liu, Yuping Zhu, Xianjun BMC Biol Research Article BACKGROUND: As the most abundant epigenetic modification of eukaryotic mRNA, N6-methyladenosine (m6A) modification has been shown to play a role in mammalian nervous system development and function by regulating mRNA synthesis and degeneration. However, the role of m6A modification in retinal photoreceptors remains unknown. RESULTS: We generated the first retina-specific Mettl14-knockout mouse models using the Rho-Cre and HRGP-Cre lines and investigated the functions of Mettl14 in retinal rod and cone photoreceptors. Our data showed that loss of Mettl14 in rod cells causes a weakened scotopic photoresponse and rod degeneration. Further study revealed the ectopic accumulation of multiple outer segment (OS) proteins in the inner segment (IS). Deficiency of Mettl14 in cone cells led to the mislocalization of cone opsin proteins and the progressive death of cone cells. Moreover, Mettl14 depletion resulted in drastic decreases in METTL3/WTAP levels and reduced m6A methylation levels. Mechanistically, transcriptomic analyses in combination with MeRIP-seq illustrated that m6A depletion via inactivation of Mettl14 resulted in reduced expression levels of multiple phototransduction- and cilium-associated genes, which subsequently led to compromised ciliogenesis and impaired synthesis and transport of OS-residing proteins in rod cells. CONCLUSIONS: Our data demonstrate that Mettl14 plays an important role in regulating phototransduction and ciliogenesis events and is essential for photoreceptor function and survival, highlighting the importance of m6A modification in visual function. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12915-022-01335-x. BioMed Central 2022-06-13 /pmc/articles/PMC9195452/ /pubmed/35698136 http://dx.doi.org/10.1186/s12915-022-01335-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research Article
Yang, Yeming
Shuai, Ping
Li, Xiao
Sun, Kuanxiang
Jiang, Xiaoyan
Liu, Wenjing
Le, Weidong
Jiang, Haisong
Liu, Yuping
Zhu, Xianjun
Mettl14-mediated m6A modification is essential for visual function and retinal photoreceptor survival
title Mettl14-mediated m6A modification is essential for visual function and retinal photoreceptor survival
title_full Mettl14-mediated m6A modification is essential for visual function and retinal photoreceptor survival
title_fullStr Mettl14-mediated m6A modification is essential for visual function and retinal photoreceptor survival
title_full_unstemmed Mettl14-mediated m6A modification is essential for visual function and retinal photoreceptor survival
title_short Mettl14-mediated m6A modification is essential for visual function and retinal photoreceptor survival
title_sort mettl14-mediated m6a modification is essential for visual function and retinal photoreceptor survival
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9195452/
https://www.ncbi.nlm.nih.gov/pubmed/35698136
http://dx.doi.org/10.1186/s12915-022-01335-x
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