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

Publisher: BioMed Central Country of Publication: England NLM ID: 101190720 Publication Model: Electronic Cited Medium: Internet ISSN: 1741-7007 (Electronic) Linking ISSN: 17417007 NLM ISO Abbreviation: BMC Biol Subsets: MEDLINE

Original Publication: [London] : BioMed Central, c2003-

Photoreceptor Cells, Vertebrate*/metabolism ; Retina*/metabolism; Methyltransferases/*metabolism; Animals ; Mammals/genetics ; Methylation ; Methyltransferases/genetics ; Mice ; Proteins/metabolism ; RNA, Messenger/metabolism ; Retinal Cone Photoreceptor Cells

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.
(© 2022. The Author(s).)

Graefes Arch Clin Exp Ophthalmol. 2005 Mar;243(3):235-42. (PMID: 15452722)
Nature. 2018 Nov;563(7730):249-253. (PMID: 30401835)
Nat Chem Biol. 2014 Feb;10(2):93-5. (PMID: 24316715)
Mol Cell. 2013 Jan 10;49(1):18-29. (PMID: 23177736)
Nature. 2017 Aug 17;548(7667):338-342. (PMID: 28792938)
Nat Rev Mol Cell Biol. 2007 Nov;8(11):880-93. (PMID: 17955020)
Prog Retin Eye Res. 2010 Sep;29(5):335-75. (PMID: 20362068)
Nat New Biol. 1972 Jan 26;235(56):114. (PMID: 4501194)
Cell Res. 2017 Sep;27(9):1115-1127. (PMID: 28809393)
Ophthalmic Genet. 2007 Sep;28(3):113-25. (PMID: 17896309)
Brain Res Bull. 2010 Apr 29;82(1-2):18-24. (PMID: 20206241)
Genome Biol. 2018 May 31;19(1):69. (PMID: 29855337)
Vision Res. 2007 Mar;47(5):624-33. (PMID: 17267005)
Mol Cell. 2016 Jul 21;63(2):306-317. (PMID: 27373337)
Cold Spring Harb Perspect Med. 2014 Oct 10;5(10):. (PMID: 25304133)
Sci Signal. 2012 Aug 14;5(237):ra58. (PMID: 22894835)
Adv Exp Med Biol. 2020;1253:3-55. (PMID: 32445090)
J Neurochem. 2019 Feb;148(3):400-412. (PMID: 30548540)
Invest Ophthalmol Vis Sci. 2014 Dec 30;55(12):8653-66. (PMID: 25550383)
J Biol Chem. 1996 Jan 19;271(3):1797-804. (PMID: 8576185)
Exp Eye Res. 2015 Jun;135:1-13. (PMID: 25887293)
Mol Cell. 2019 May 16;74(4):640-650. (PMID: 31100245)
Nat Neurosci. 2011 Jun 05;14(7):874-80. (PMID: 21642972)
Cell. 2015 Jun 4;161(6):1388-99. (PMID: 26046440)
Br J Ophthalmol. 2016 Apr;100(4):495-500. (PMID: 26472407)
Prog Retin Eye Res. 2008 Mar;27(2):213-35. (PMID: 18328765)
Front Cell Dev Biol. 2021 Feb 04;9:636737. (PMID: 33614665)
PLoS Genet. 2017 Dec 15;13(12):e1007128. (PMID: 29244804)
Nucleic Acids Res. 2018 Feb 16;46(3):1412-1423. (PMID: 29186567)
Nat Rev Genet. 2014 May;15(5):293-306. (PMID: 24662220)
J Comp Neurol. 1979 Nov 15;188(2):245-62. (PMID: 500858)
Dev Biol. 2002 Apr 15;244(2):305-18. (PMID: 11944939)
Mol Cell. 2016 Feb 18;61(4):507-519. (PMID: 26876937)
J Cell Biol. 2010 Jun 14;189(6):1039-51. (PMID: 20530210)
Biol Cell. 2011 Oct 1;103(10):449-66. (PMID: 21732910)
Hum Mutat. 2007 Mar;28(3):243-54. (PMID: 17044014)
Dev Biol. 2000 Jun 15;222(2):460-70. (PMID: 10837133)
Nat Rev Mol Cell Biol. 2017 Jan;18(1):31-42. (PMID: 27808276)
Cytoskeleton (Hoboken). 2011 Nov;68(11):619-27. (PMID: 21976302)
Cell Res. 2014 Feb;24(2):177-89. (PMID: 24407421)
Genesis. 2005 Feb;41(2):73-80. (PMID: 15682388)
J Cell Biol. 2007 Oct 22;179(2):321-30. (PMID: 17954613)
Prog Retin Eye Res. 2019 Jul;71:26-56. (PMID: 30590118)
Nat Genet. 1996 Jul;13(3):358-60. (PMID: 8673138)
N Engl J Med. 1990 Nov 8;323(19):1302-7. (PMID: 2215617)
Sci Rep. 2020 Sep 16;10(1):15156. (PMID: 32938956)
J Biol Chem. 2016 Mar 25;291(13):7142-55. (PMID: 26814127)
Nat Chem Biol. 2011 Oct 16;7(12):885-7. (PMID: 22002720)
Cell. 1975 Apr;4(4):379-86. (PMID: 164293)
Hum Mol Genet. 2017 Jul 1;26(13):2398-2411. (PMID: 28398475)
Cell. 1974 Nov;3(3):197-9. (PMID: 4373171)
Cell Res. 2017 Mar;27(3):315-328. (PMID: 28106072)
Cell Res. 2019 Jan;29(1):23-41. (PMID: 30514900)
Nature. 2012 Apr 29;485(7397):201-6. (PMID: 22575960)
J Comp Neurol. 1984 Mar 20;224(1):71-84. (PMID: 6715580)
Genome Biol. 2018 May 31;19(1):68. (PMID: 29855379)
Cell. 2012 Jun 22;149(7):1635-46. (PMID: 22608085)
Nature. 2016 May 25;534(7608):575-8. (PMID: 27281194)
Cell. 2017 Nov 2;171(4):877-889.e17. (PMID: 28965759)
Cell. 2012 Aug 3;150(3):533-48. (PMID: 22863007)
PLoS Comput Biol. 2020 Mar 9;16(3):e1007691. (PMID: 32150546)
Nat Cell Biol. 2014 Feb;16(2):191-8. (PMID: 24394384)
Mol Vis. 2020 Oct 10;26:705-717. (PMID: 33088174)
Prog Retin Eye Res. 2013 Sep;36:24-51. (PMID: 23562855)
PLoS Biol. 2018 Jun 7;16(6):e2004880. (PMID: 29879109)
Hum Mol Genet. 2012 Nov 1;21(21):4573-86. (PMID: 22791751)
PLoS One. 2013 May 22;8(5):e64873. (PMID: 23717670)
Organogenesis. 2014 Jan 1;10(1):69-85. (PMID: 24162842)
Proc Natl Acad Sci U S A. 2014 Jul 15;111(28):E2841-50. (PMID: 24982133)
Nature. 2014 Jan 2;505(7481):117-20. (PMID: 24284625)

Keywords: Ciliogenesis; METTL14; N6-methyladenosine; Photoreceptor degeneration; Phototransduction

0 (Proteins)
0 (RNA, Messenger)
EC 2.1.1.- (Methyltransferases)
EC 2.1.1.- (Mettl14 protein, mouse)

Date Created: 20220613 Date Completed: 20220615 Latest Revision: 20220725

20240628

PMC9195452

10.1186/s12915-022-01335-x

35698136