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Cited by 16RNA modifications and cancerRetinal Development and DisordersNeurogenesis and neuroplasticity mechanisms

m6A epitranscriptomic modification regulates neural progenitor-to-glial cell transition in the retina

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Xin, Yanling, He, Qinghai, Liang, Huilin, Zhang, Ke, Guo, Jingyi, Zhong, Qi, Chen, Dan, Li, Jinyan +2 more·2022·eLife
DOI 10.7554/elife.79994PMC PMC9718531

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Abstract

N 6 -methyladenosine (m 6 A) is the most prevalent mRNA internal modification and has been shown to regulate the development, physiology, and pathology of various tissues. However, the functions of the m 6 A epitranscriptome in the visual system remain unclear. In this study, using a retina-specific conditional knockout mouse model, we show that retinas deficient in Mettl3 , the core component of the m 6 A methyltransferase complex, exhibit structural and functional abnormalities beginning at the end of retinogenesis. Immunohistological and single-cell RNA sequencing (scRNA-seq) analyses of retinogenesis processes reveal that retinal progenitor cells (RPCs) and Müller glial cells are the two cell types primarily affected by Mettl3 deficiency. Integrative analyses of scRNA-seq and MeRIP-seq data suggest that m 6 A fine-tunes the transcriptomic transition from RPCs to Müller cells by promoting the degradation of RPC transcripts, the disruption of which leads to abnormalities in late retinogenesis and likely compromises the glial functions of Müller cells. Overexpression of m 6 A-regulated RPC transcripts in late RPCs partially recapitulates the Mettl3 -deficient retinal phenotype. Collectively, our study reveals an epitranscriptomic mechanism governing progenitor-to-glial cell transition during late retinogenesis, which is essential for the homeostasis of the mature retina. The mechanism revealed in this study might also apply to other nervous systems.

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  • Overexpression of Zfp292 phenocopied the effects of Mettl3 and Mettl14 inactivation in late RPCs.

    “Overexpression of Zfp292 phenocopied the effects of Mettl3 and Mettl14 inactivation in late RPCs (Xin et al., 2022; Li et al., 2023).”

    From METTL3 uncouples chromatin accessibility from transcription during retinal development (2025) · cites this paper as Xin et al., 2022

    The Results section reports that Zfp292 overexpression delayed cell-cycle exit and increased Müller glial fate in late RPCs, effects that overlap with those reported for Mettl3 deficiency. But the Discussion explicitly says overexpression did not faithfully recapitulate the Mettl3-knockout cell-population phenotype, and the passages found do not establish the claimed comparison with Mettl14 inactivation. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Zfp292 showed the highest reduction in m6A in both SIX3+ RPCs with Mettl3 deletion and CHX10+ RPCs with Mettl14 loss.

    “Zfp292, which inhibits cell cycle progression, showed the highest reduction in m6A in both SIX3+ RPCs with Mettl3 deletion and CHX10+ RPCs with Mettl14 loss.”

    From METTL3 uncouples chromatin accessibility from transcription during retinal development (2025) · cites this paper as Xin et al., 2022

    The Results section, “Overexpression of m6A-tagged RPC genes in late RPCs disturbs late-stage retinogenesis” (page unavailable), identifies Zfp292 among transcripts with reduced m6A modification in Mettl3-CKO retinas. It does not establish that Zfp292 had the highest reduction, or report that result specifically in SIX3+ RPCs or in CHX10+ RPCs with Mettl14 loss. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • In mice, Mettl3 loss leads to abnormalities in RPC-to-Müller glia transition in late retinogenesis due to increased half-life and reduced m6A of RPC transcripts.

    “In mice, Mettl3 loss leads to abnormalities in RPC-to-Müller glia transition in late retinogenesis due to increased half-life and reduced m6A of RPC transcripts (Xin et al., 2022).”

    From METTL3 uncouples chromatin accessibility from transcription during retinal development (2025) · cites this paper as Xin et al., 2022

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Research works printed but not linked: 55

  1. Agathocleous M Harris WA 2009 From progenitors to differentiated cells in the vertebrate retina Annual Review of Cell and Developmental Biology 25 45 69 10.1146/annurev.cellbio.042308.113259 19575661 · DOI
  2. Allen NJ Lyons DA 2018 Glia as architects of central nervous system formation and function Science 362 181 185 10.1126/science.aat0473 30309945 PMC6292669 · DOI · Paper page
  3. Bassett EA Wallace VA 2012 Cell fate determination in the vertebrate retina Trends in Neurosciences 35 565 573 10.1016/j.tins.2012.05.004 22704732 · DOI
  4. Blackshaw S Harpavat S Trimarchi J Cai L Huang H Kuo WP Weber G Lee K Fraioli RE Cho SH Yung R Asch E Ohno-Machado L Wong WH Cepko CL 2004 Genomic analysis of mouse retinal development PLOS Biology 2 E247 10.1371/journal.pbio.0020247 15226823 PMC439783 · DOI
  5. Bokar JA Rath-Shambaugh ME Ludwiczak R Narayan P Rottman F 1994 Characterization and partial purification of mrna N6-adenosine methyltransferase from hela cell nuclei. Internal mrna methylation requires a multisubunit complex The Journal of Biological Chemistry 269 17697 17704 10.1016/S0021-9258(17)32497-3 8021282 · DOI · Paper page
  6. Bokar JA Shambaugh ME Polayes D Matera AG Rottman FM 1997 Purification and cdna cloning of the adomet-binding subunit of the human mrna (N6-adenosine) -methyltransferase RNA 3 1233 1247 9409616 PMC1369564
  7. Byrne LC Khalid F Lee T Zin EA Greenberg KP Visel M Schaffer DV Flannery JG 2013 Aav-Mediated, optogenetic ablation of Müller glia leads to structural and functional changes in the mouse retina PLOS ONE 8 e76075 10.1371/journal.pone.0076075 24086689 PMC3785414 · DOI
  8. Cepko C 2014 Intrinsically different retinal progenitor cells produce specific types of progeny Nature Reviews. Neuroscience 15 615 627 10.1038/nrn3767 25096185 · DOI
  9. Chen C-YA Ezzeddine N Shyu A-B 2008 Messenger RNA half-life measurements in mammalian cells Methods in Enzymology 448 335 357 10.1016/S0076-6879(08)02617-7 19111184 PMC2778729 · DOI · Paper page
  10. Clark BS Stein-O’Brien GL Shiau F Cannon GH Davis-Marcisak E Sherman T Santiago CP Hoang TV Rajaii F James-Esposito RE Gronostajski RM Fertig EJ Goff LA Blackshaw S 2019 Single-Cell RNA-seq analysis of retinal development identifies NFI factors as regulating mitotic exit and late-born cell specification Neuron 102 1111 1126 10.1016/j.neuron.2019.04.010 31128945 PMC6768831 · DOI
  11. Dominissini D Moshitch-Moshkovitz S Schwartz S Salmon-Divon M Ungar L Osenberg S Cesarkas K Jacob-Hirsch J Amariglio N Kupiec M Sorek R Rechavi G 2012 Topology of the human and mouse m6a RNA methylomes revealed by m6a-seq Nature 485 201 206 10.1038/nature11112 22575960 · DOI · Paper page
  12. Dominissini D Moshitch-Moshkovitz S Salmon-Divon M Amariglio N Rechavi G 2013 Transcriptome-Wide mapping of N6-methyladenosine by m6a-seq based on immunocapturing and massively parallel sequencing Nature Protocols 8 176 189 10.1038/nprot.2012.148 23288318 · DOI
  13. Frye M Blanco S 2016 Post-Transcriptional modifications in development and stem cells Development 143 3871 3881 10.1242/dev.136556 27803056 · DOI
  14. Furuta Y Lagutin O Hogan BL Oliver GC 2000 Retina- and ventral forebrain-specific cre recombinase activity in transgenic mice Genesis 26 130 132 10.1002/(SICI)1526-968X(200002)26:2<130::AID-GENE9>3.0.CO;2-I 10686607 · DOI
  15. Goldman D 2014 Müller glial cell reprogramming and retina regeneration Nature Reviews Neuroscience 15 431 442 10.1038/nrn3723 24894585 PMC4249724 · DOI
  16. Guo Z Zhang L Wu Z Chen Y Wang F Chen G 2014 In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model Cell Stem Cell 14 188 202 10.1016/j.stem.2013.12.001 24360883 PMC3967760 · DOI
  17. Heavner W Pevny L 2012 Eye development and retinogenesis Cold Spring Harbor Perspectives in Biology 4 a008391 10.1101/cshperspect.a008391 23071378 PMC3504437 · DOI
  18. Hoang T Wang J Boyd P Wang F Santiago C Jiang L Yoo S Lahne M Todd LJ Jia M Saez C Keuthan C Palazzo I Squires N Campbell WA Rajaii F Parayil T Trinh V Kim DW Wang G Campbell LJ Ash J Fischer AJ Hyde DR Qian J Blackshaw S 2020 Gene regulatory networks controlling vertebrate retinal regeneration Science 370 eabb8598 10.1126/science.abb8598 33004674 PMC7899183 · DOI
  19. Huang L Liang H Wang S Chen S 2021 M6A writer complex promotes timely differentiation and survival of retinal progenitor cells in zebrafish Biochemical and Biophysical Research Communications 567 171 176 10.1016/j.bbrc.2021.06.043 34166914 · DOI · Paper page
  20. Jadhav AP Roesch K Cepko CL 2009 Development and neurogenic potential of Müller glial cells in the vertebrate retina Progress in Retinal and Eye Research 28 249 262 10.1016/j.preteyeres.2009.05.002 19465144 PMC3233204 · DOI
  21. Jia G Fu Y Zhao X Dai Q Zheng G Yang Y Yi C Lindahl T Pan T Yang YG He C 2011 N6-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO Nature Chemical Biology 7 885 887 10.1038/nchembio.687 22002720 PMC3218240 · DOI · Paper page
  22. Jorstad NL Wilken MS Grimes WN Wohl SG VandenBosch LS Yoshimatsu T Wong RO Rieke F Reh TA 2017 Stimulation of functional neuronal regeneration from Müller glia in adult mice Nature 548 103 107 10.1038/nature23283 28746305 PMC5991837 · DOI
  23. Lahne M Nagashima M Hyde DR Hitchcock PF 2020 Reprogramming Müller glia to regenerate retinal neurons Annual Review of Vision Science 6 171 193 10.1146/annurev-vision-121219-081808 32343929 PMC8384111 · DOI
  24. Lee Y Choe J Park OH Kim YK 2020 Molecular mechanisms driving mRNA degradation by M6a modification Trends in Genetics 36 177 188 10.1016/j.tig.2019.12.007 31964509 · DOI
  25. Lin Z Hsu PJ Xing X Fang J Lu Z Zou Q Zhang KJ Zhang X Zhou Y Zhang T Zhang Y Song W Jia G Yang X He C Tong MH 2017 Mettl3-/mettl14-mediated mRNA N6-methyladenosine modulates murine spermatogenesis Cell Research 27 1216 1230 10.1038/cr.2017.117 28914256 PMC5630681 · DOI
  26. Lin S Guo J Chen S 2019 Transcriptome and DNA methylome signatures associated with retinal Müller glia development, injury response, and aging Investigative Ophthalmology & Visual Science 60 4436 4450 10.1167/iovs.19-27361 31652328 · DOI
  27. Liu J Yue Y Han D Wang X Fu Y Zhang L Jia G Yu M Lu Z Deng X Dai Q Chen W He C 2014 A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation Nature Chemical Biology 10 93 95 10.1038/nchembio.1432 24316715 PMC3911877 · DOI · Paper page
  28. Liu J Harada BT He C 2019 Regulation of gene expression by N-methyladenosine in cancer Trends in Cell Biology 29 487 499 10.1016/j.tcb.2019.02.008 30940398 PMC6527461 · DOI
  29. MacDonald RB Randlett O Oswald J Yoshimatsu T Franze K Harris WA 2015 Müller glia provide essential tensile strength to the developing retina The Journal of Cell Biology 210 1075 1083 10.1083/jcb.201503115 26416961 PMC4586739 · DOI
  30. MacDonald RB Charlton-Perkins M Harris WA 2017 Mechanisms of Müller glial cell morphogenesis Current Opinion in Neurobiology 47 31 37 10.1016/j.conb.2017.08.005 28850820 · DOI
  31. Masland RH 2001 The fundamental plan of the retina Nature Neuroscience 4 877 886 10.1038/nn0901-877 11528418 · DOI
  32. Meyer KD Saletore Y Zumbo P Elemento O Mason CE Jaffrey SR 2012 Comprehensive analysis of mRNA methylation reveals enrichment in 3’ UTRs and near stop codons Cell 149 1635 1646 10.1016/j.cell.2012.05.003 22608085 PMC3383396 · DOI · Paper page
  33. Meyer KD Jaffrey SR 2014 The dynamic epitranscriptome: N6-methyladenosine and gene expression control Nature Reviews. Molecular Cell Biology 15 313 326 10.1038/nrm3785 24713629 PMC4393108 · DOI
  34. Meyer KD Jaffrey SR 2017 Rethinking m(6)A readers, writers, and erasers Annual Review of Cell and Developmental Biology 33 319 342 10.1146/annurev-cellbio-100616-060758 PMC5963928 28759256 · DOI
  35. Nelson BR Ueki Y Reardon S Karl MO Georgi S Hartman BH Lamba DA Reh TA 2011 Genome-Wide analysis of Müller glial differentiation reveals a requirement for Notch signaling in postmitotic cells to maintain the glial fate PLOS ONE 6 e22817 10.1371/journal.pone.0022817 21829655 PMC3149061 · DOI
  36. Newman E Reichenbach A 1996 The Müller cell: a functional element of the retina Trends in Neurosciences 19 307 312 10.1016/0166-2236(96)10040-0 8843598 · DOI
  37. Qian H Kang X Hu J Zhang D Liang Z Meng F Zhang X Xue Y Maimon R Dowdy SF Devaraj NK Zhou Z Mobley WC Cleveland DW Fu XD 2020 Reversing a model of Parkinson’s disease with in situ converted nigral neurons Nature 582 550 556 10.1038/s41586-020-2388-4 32581380 PMC7521455 · DOI · Paper page
  38. Roesch K Jadhav AP Trimarchi JM Stadler MB Roska B Sun BB Cepko CL 2008 The transcriptome of retinal Müller glial cells The Journal of Comparative Neurology 509 225 238 10.1002/cne.21730 18465787 PMC2665263 · DOI
  39. Roundtree IA Evans ME Pan T He C 2017 Dynamic RNA modifications in gene expression regulation Cell 169 1187 1200 10.1016/j.cell.2017.05.045 28622506 PMC5657247 · DOI
  40. Shen W Fruttiger M Zhu L Chung SH Barnett NL Kirk JK Lee S Coorey NJ Killingsworth M Sherman LS Gillies MC 2012 Conditional müllercell ablation causes independent neuronal and vascular pathologies in a novel transgenic model The Journal of Neuroscience 32 15715 15727 10.1523/JNEUROSCI.2841-12.2012 23136411 PMC4014009 · DOI
  41. Shi H Wei J He C 2019 Where, when, and how: context-dependent functions of RNA methylation writers, readers, and erasers Molecular Cell 74 640 650 10.1016/j.molcel.2019.04.025 31100245 PMC6527355 · DOI
  42. Sledź P Jinek M 2016 Structural insights into the molecular mechanism of the M (6) a writer complex eLife 5 e18434 10.7554/eLife.18434 27627798 PMC5023411 · DOI
  43. Vázquez-Chona FR Clark AM Levine EM 2009 Rlbp1 promoter drives robust Müller glial GFP expression in transgenic mice Investigative Ophthalmology & Visual Science 50 3996 4003 10.1167/iovs.08-3189 19324864 · DOI
  44. Vecino E Rodriguez FD Ruzafa N Pereiro X Sharma SC 2016 Glia-Neuron interactions in the mammalian retina Progress in Retinal and Eye Research 51 1 40 10.1016/j.preteyeres.2015.06.003 26113209 · DOI
  45. Wang P Doxtader KA Nam Y 2016a Structural basis for cooperative function of METTL3 and mettl14 methyltransferases Molecular Cell 63 306 317 10.1016/j.molcel.2016.05.041 27373337 PMC4958592 · DOI
  46. Wang X Feng J Xue Y Guan Z Zhang D Liu Z Gong Z Wang Q Huang J Tang C Zou T Yin P 2016b Structural basis of N (6) -adenosine methylation by the METTL3-METTL14 complex Nature 534 575 578 10.1038/nature18298 27281194 · DOI
  47. Wang J O’Sullivan ML Mukherjee D Puñal VM Farsiu S Kay JN 2017 Anatomy and spatial organization of Müller glia in mouse retina The Journal of Comparative Neurology 525 1759 1777 10.1002/cne.24153 27997986 PMC5542564 · DOI
  48. Wang Y Li Y Yue M Wang J Kumar S Wechsler-Reya RJ Zhang Z Ogawa Y Kellis M Duester G Zhao JC 2018 N6-Methyladenosine RNA modification regulates embryonic neural stem cell self-renewal through histone modifications Nature Neuroscience 21 195 206 10.1038/s41593-017-0057-1 29335608 PMC6317335 · DOI
  49. Wohl SG Jorstad NL Levine EM Reh TA 2017 Müller glial microRNAs are required for the maintenance of glial homeostasis and retinal architecture Nature Communications 8 1603 10.1038/s41467-017-01624-y 29150673 PMC5693933 · DOI
  50. Yao K Qiu S Wang YV Park SJH Mohns EJ Mehta B Liu X Chang B Zenisek D Crair MC Demb JB Chen B 2018 Restoration of vision after de novo genesis of rod photoreceptors in mammalian retinas Nature 560 484 488 10.1038/s41586-018-0425-3 30111842 PMC6107416 · DOI · Paper page
  51. Yoon K-J Ringeling FR Vissers C Jacob F Pokrass M Jimenez-Cyrus D Su Y Kim N-S Zhu Y Zheng L Kim S Wang X Doré LC Jin P Regot S Zhuang X Canzar S He C Ming G-L Song H 2017 Temporal control of mammalian cortical neurogenesis by M6a methylation Cell 171 877 889 10.1016/j.cell.2017.09.003 28965759 PMC5679435 · DOI
  52. Yu G Wang LG Han Y He QY 2012 ClusterProfiler: an R package for comparing biological themes among gene clusters OMICS 16 284 287 10.1089/omi.2011.0118 22455463 PMC3339379 · DOI · Paper page
  53. Zhao BS Roundtree IA He C 2017 Post-Transcriptional gene regulation by mRNA modifications Nature Reviews. Molecular Cell Biology 18 31 42 10.1038/nrm.2016.132 27808276 PMC5167638 · DOI
  54. Zheng G Dahl JA Niu Y Fedorcsak P Huang C-M Li CJ Vågbø CB Shi Y Wang W-L Song S-H Lu Z Bosmans RPG Dai Q Hao Y-J Yang X Zhao W-M Tong W-M Wang X-J Bogdan F Furu K Fu Y Jia G Zhao X Liu J Krokan HE Klungland A Yang Y-G He C 2013 Alkbh5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility Molecular Cell 49 18 29 10.1016/j.molcel.2012.10.015 23177736 PMC3646334 · DOI · Paper page
  55. Zhou H Su J Hu X Zhou C Li H Chen Z Xiao Q Wang B Wu W Sun Y Zhou Y Tang C Liu F Wang L Feng C Liu M Li S Zhang Y Xu H Yao H Shi L Yang H 2020 Glia-to-neuron conversion by CRISPR-casrx alleviates symptoms of neurological disease in mice Cell 181 590 603 10.1016/j.cell.2020.03.024 32272060 · DOI · Paper page

Cited by

Sorted by citations

Authors
Xin, Y., He, Q., Liang, H., Zhang, K., Guo, J., Zhong, Q., Chen, D., Li, J., Liu, Y., & Chen, S.
Affiliations
State Key Laboratory of Ophthalmology (CN)
Corresponding author
Chen, Shuyi
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2022-12-02
Volume
11
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.79994
PMC
PMC9718531
OpenAlex
W4310960919
Cited by
16
References
5
Citations by year
2026: 5 · 2025: 5 · 2024: 2 · 2023: 3 · 2022: 1
FWCI
0.90
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (81870659, 81721003)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
N6-methyladenosine, m6A epitranscriptome, METTL3, retinal development, retinal progenitor cells, Müller cells, mRNA degradation, MeRIP-seq, single-cell RNA sequencing
MeSH terms
Animals, Homeostasis, Neuroglia, Retina, Mice, Knockout, Mice, Neural Stem Cells, Ependymoglial Cells

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