The nanophthalmos protein TMEM98 inhibits MYRF self-cleavage and is required for eye size specification
Autoři:
Sally H. Cross aff001; Lisa Mckie aff001; Toby W. Hurd aff001; Sam Riley aff001; Jimi Wills aff001; Alun R. Barnard aff002; Fiona Young aff003; Robert E. MacLaren aff002; Ian J. Jackson aff001
Působiště autorů:
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
aff001; Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, The John Radcliffe Hospital, Oxford, United Kingdom
aff002; Electron Microscopy, Pathology, Western General Hospital, Edinburgh, United Kingdom
aff003; Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, United Kingdom
aff004
Vyšlo v časopise:
The nanophthalmos protein TMEM98 inhibits MYRF self-cleavage and is required for eye size specification. PLoS Genet 16(4): e32767. doi:10.1371/journal.pgen.1008583
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1008583
Souhrn
The precise control of eye size is essential for normal vision. TMEM98 is a highly conserved and widely expressed gene which appears to be involved in eye size regulation. Mutations in human TMEM98 are found in patients with nanophthalmos (very small eyes) and variants near the gene are associated in population studies with myopia and increased eye size. As complete loss of function mutations in mouse Tmem98 result in perinatal lethality, we produced mice deficient for Tmem98 in the retinal pigment epithelium (RPE), where Tmem98 is highly expressed. These mice have greatly enlarged eyes that are very fragile with very thin retinas, compressed choroid and thin sclera. To gain insight into the mechanism of action we used a proximity labelling approach to discover interacting proteins and identified MYRF as an interacting partner. Mutations of MYRF are also associated with nanophthalmos. The protein is an endoplasmic reticulum-tethered transcription factor which undergoes autoproteolytic cleavage to liberate the N-terminal part which then translocates to the nucleus where it acts as a transcription factor. We find that TMEM98 inhibits the self-cleavage of MYRF, in a novel regulatory mechanism. In RPE lacking TMEM98, MYRF is ectopically activated and abnormally localised to the nuclei. Our findings highlight the importance of the interplay between TMEM98 and MYRF in determining the size of the eye.
Klíčová slova:
Cell signaling – Cell staining – Cornea – Eyes – Immunostaining – Missense mutation – Retina – Transcription factors
Zdroje
1. Wojciechowski R. Nature and nurture: the complex genetics of myopia and refractive error. Clinical genetics. 2011;79(4):301–20. Epub 2010/12/16. doi: 10.1111/j.1399-0004.2010.01592.x 21155761; PubMed Central PMCID: PMC3058260.
2. Kiefer AK, Tung JY, Do CB, Hinds DA, Mountain JL, Francke U, et al. Genome-wide analysis points to roles for extracellular matrix remodeling, the visual cycle, and neuronal development in myopia. PLoS genetics. 2013;9(2):e1003299. doi: 10.1371/journal.pgen.1003299 23468642
3. Verhoeven VJ, Hysi PG, Wojciechowski R, Fan Q, Guggenheim JA, Hohn R, et al. Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia. Nat Genet. 2013;45(3):314–8. doi: 10.1038/ng.2554 23396134.
4. Tedja MS, Wojciechowski R, Hysi PG, Eriksson N, Furlotte NA, Verhoeven VJM, et al. Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error. Nat Genet. 2018;50(6):834–48. Epub 2018/05/29. doi: 10.1038/s41588-018-0127-7 29808027; PubMed Central PMCID: PMC5980758.
5. Pickrell JK, Berisa T, Liu JZ, Segurel L, Tung JY, Hinds DA. Detection and interpretation of shared genetic influences on 42 human traits. Nat Genet. 2016;48(7):709–17. Epub 2016/05/18. doi: 10.1038/ng.3570 27182965; PubMed Central PMCID: PMC5207801.
6. Awadalla MS, Burdon KP, Souzeau E, Landers J, Hewitt AW, Sharma S, et al. Mutation in TMEM98 in a large white kindred with autosomal dominant nanophthalmos linked to 17p12-q12. JAMA ophthalmology. 2014;132(8):970–7. Epub 2014/05/24. doi: 10.1001/jamaophthalmol.2014.946 24852644.
7. Khorram D, Choi M, Roos BR, Stone EM, Kopel T, Allen R, et al. Novel TMEM98 mutations in pedigrees with autosomal dominant nanophthalmos. Molecular vision. 2015;21:1017–23. Epub 2015/09/24. 26392740; PubMed Central PMCID: PMC4556162.
8. Imadome K, Iwakawa M, Nakawatari M, Fujita H, Kato S, Ohno T, et al. Subtypes of cervical adenosquamous carcinomas classified by EpCAM expression related to radiosensitivity. Cancer biology & therapy. 2010;10(10):1019–26. Epub 2010/09/22. doi: 10.4161/cbt.10.10.13249 20855955.
9. Ng KT, Lo CM, Guo DY, Qi X, Li CX, Geng W, et al. Identification of transmembrane protein 98 as a novel chemoresistance-conferring gene in hepatocellular carcinoma. Molecular cancer therapeutics. 2014;13(5):1285–97. Epub 2014/03/13. doi: 10.1158/1535-7163.MCT-13-0806 24608572.
10. Fu W, Cheng Y, Zhang Y, Mo X, Li T, Liu Y, et al. The Secreted Form of Transmembrane Protein 98 Promotes the Differentiation of T Helper 1 Cells. Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research. 2015;35(9):720–33. Epub 2015/05/07. doi: 10.1089/jir.2014.0110 25946230; PubMed Central PMCID: PMC4560856.
11. Mao M, Chen J, Li X, Wu Z. siRNA-TMEM98 inhibits the invasion and migration of lung cancer cells. International journal of clinical and experimental pathology. 2015;8(12):15661–9. Epub 2016/02/18. 26884835; PubMed Central PMCID: PMC4730048.
12. Lv G, Zhu H, Li C, Wang J, Zhao D, Li S, et al. Inhibition of IL-8-mediated endothelial adhesion, VSMCs proliferation and migration by siRNA-TMEM98 suggests TMEM98's emerging role in atherosclerosis. Oncotarget. 2017;8(50):88043–58. Epub 2017/11/21. doi: 10.18632/oncotarget.21408 29152140; PubMed Central PMCID: PMC5675692.
13. Tang Q, Ran H. MicroRNA-219-5p inhibits wound healing by targeting TMEM98 in keratinocytes under normoxia and hypoxia condition. European review for medical and pharmacological sciences. 2018;22(19):6205–11. Epub 2018/10/20. doi: 10.26355/eurrev_201810_16026 30338788.
14. Bliss SA, Paul S, Pobiarzyn PW, Ayer S, Sinha G, Pant S, et al. Evaluation of a developmental hierarchy for breast cancer cells to assess risk-based patient selection for targeted treatment. Sci Rep. 2018;8(1):367. Epub 2018/01/13. doi: 10.1038/s41598-017-18834-5 29321622; PubMed Central PMCID: PMC5762675.
15. Cross SH, McKie L, Keighren M, West K, Thaung C, Davey T, et al. Missense Mutations in the Human Nanophthalmos Gene TMEM98 Cause Retinal Defects in the Mouse. Investigative ophthalmology & visual science. 2019;60(8):2875–87. Epub 2019/07/03. doi: 10.1167/iovs.18-25954 31266059.
16. Marmorstein LY, Wu J, McLaughlin P, Yocom J, Karl MO, Neussert R, et al. The light peak of the electroretinogram is dependent on voltage-gated calcium channels and antagonized by bestrophin (best-1). The Journal of general physiology. 2006;127(5):577–89. doi: 10.1085/jgp.200509473 16636205
17. Milenkovic A, Brandl C, Milenkovic VM, Jendryke T, Sirianant L, Wanitchakool P, et al. Bestrophin 1 is indispensable for volume regulation in human retinal pigment epithelium cells. Proceedings of the National Academy of Sciences. 2015;112(20):E2630–E9.
18. Zhang Y, Stanton JB, Wu J, Yu K, Hartzell HC, Peachey NS, et al. Suppression of Ca 2+ signaling in a mouse model of Best disease. Human molecular genetics. 2010;19(6):1108–18. doi: 10.1093/hmg/ddp583 20053664
19. Mehalow AK, Kameya S, Smith RS, Hawes NL, Denegre JM, Young JA, et al. CRB1 is essential for external limiting membrane integrity and photoreceptor morphogenesis in the mammalian retina. Human molecular genetics. 2003;12(17):2179–89. doi: 10.1093/hmg/ddg232 12915475
20. van de Pavert SA, Kantardzhieva A, Malysheva A, Meuleman J, Versteeg I, Levelt C, et al. Crumbs homologue 1 is required for maintenance of photoreceptor cell polarization and adhesion during light exposure. Journal of Cell Science. 2004;117(18):4169–77.
21. van de Pavert SA, Meuleman J, Malysheva A, Aartsen WM, Versteeg I, Tonagel F, et al. A single amino acid substitution (Cys249Trp) in Crb1 causes retinal degeneration and deregulates expression of pituitary tumor transforming gene Pttg1. Journal of Neuroscience. 2007;27(3):564–73. doi: 10.1523/JNEUROSCI.3496-06.2007 17234588
22. Fogerty J, Besharse JC. 174delG mutation in mouse MFRP causes photoreceptor degeneration and RPE atrophy. Investigative ophthalmology & visual science. 2011;52(10):7256–66.
23. Kameya S, Hawes NL, Chang B, Heckenlively JR, Naggert JK, Nishina PM. Mfrp, a gene encoding a frizzled related protein, is mutated in the mouse retinal degeneration 6. Human molecular genetics. 2002;11(16):1879–86. doi: 10.1093/hmg/11.16.1879 12140190
24. Hawes NL, Chang B, Hageman GS, Nusinowitz S, Nishina PM, Schneider BS, et al. Retinal degeneration 6 (rd6): a new mouse model for human retinitis punctata albescens. Investigative ophthalmology & visual science. 2000;41(10):3149–57.
25. Velez G, Tsang SH, Tsai Y-T, Hsu C-W, Gore A, Abdelhakim AH, et al. Gene Therapy Restores Mfrp and Corrects Axial Eye Length. Scientific Reports. 2017;7(1):16151. doi: 10.1038/s41598-017-16275-8 29170418
26. Nair KS, Hmani-Aifa M, Ali Z, Kearney AL, Salem SB, Macalinao DG, et al. Alteration of the serine protease PRSS56 causes angle-closure glaucoma in mice and posterior microphthalmia in humans and mice. Nature Genetics. 2011;43:579. doi: 10.1038/ng.813 21532570
27. Paylakhi S, Labelle-Dumais C, Tolman NG, Sellarole MA, Seymens Y, Saunders J, et al. Muller glia-derived PRSS56 is required to sustain ocular axial growth and prevent refractive error. PLoS Genet. 2018;14(3):e1007244. doi: 10.1371/journal.pgen.1007244 29529029.
28. Garnai SJ, Brinkmeier ML, Emery B, Aleman TS, Pyle LC, Veleva-Rotse B, et al. Variants in myelin regulatory factor (MYRF) cause autosomal dominant and syndromic nanophthalmos in humans and retinal degeneration in mice. PLoS Genet. 2019;15(5):e1008130. Epub 2019/05/03. doi: 10.1371/journal.pgen.1008130 31048900.
29. Guo C, Zhao Z, Chen D, He S, Sun N, Li Z, et al. Detection of Clinically Relevant Genetic Variants in Chinese Patients With Nanophthalmos by Trio-Based Whole-Genome Sequencing Study. Investigative ophthalmology & visual science. 2019;60(8):2904–13. Epub 2019/07/03. doi: 10.1167/iovs.18-26275 31266062.
30. Xiao X, Sun W, Ouyang J, Li S, Jia X, Tan Z, et al. Novel truncation mutations in MYRF cause autosomal dominant high hyperopia mapped to 11p12-q13.3. Human genetics. 2019;138(10):1077–90. Epub 2019/06/07. doi: 10.1007/s00439-019-02039-z 31172260; PubMed Central PMCID: PMC6745028.
31. Siggs OM, Souzeau E, Breen J, Qassim A, Zhou T, Dubowsky A, et al. Autosomal dominant nanophthalmos and high hyperopia associated with a C-terminal frameshift variant in MYRF. Molecular vision. 2019;25:527–34. Epub 2019/11/09. 31700225; PubMed Central PMCID: PMC6817736.
32. Kluppel M, Beermann F, Ruppert S, Schmid E, Hummler E, Schutz G. The mouse tyrosinase promoter is sufficient for expression in melanocytes and in the pigmented epithelium of the retina. Proceedings of the National Academy of Sciences of the United States of America. 1991;88(9):3777–81. Epub 1991/05/01. doi: 10.1073/pnas.88.9.3777 1902569; PubMed Central PMCID: PMC51536.
33. Delmas V, Martinozzi S, Bourgeois Y, Holzenberger M, Larue L. Cre-mediated recombination in the skin melanocyte lineage. Genesis (New York, NY: 2000). 2003;36(2):73–80. Epub 2003/06/24. doi: 10.1002/gene.10197 12820167.
34. Muzumdar MD, Tasic B, Miyamichi K, Li L, Luo L. A global double-fluorescent Cre reporter mouse. Genesis (New York, NY: 2000). 2007;45(9):593–605. Epub 2007/09/18. doi: 10.1002/dvg.20335 17868096.
35. Stevenson BR, Siliciano JD, Mooseker MS, Goodenough DA. Identification of ZO-1: a high molecular weight polypeptide associated with the tight junction (zonula occludens) in a variety of epithelia. The Journal of cell biology. 1986;103(3):755–66. Epub 1986/09/01. doi: 10.1083/jcb.103.3.755 3528172; PubMed Central PMCID: PMC2114282.
36. Longbottom R, Fruttiger M, Douglas RH, Martinez-Barbera JP, Greenwood J, Moss SE. Genetic ablation of retinal pigment epithelial cells reveals the adaptive response of the epithelium and impact on photoreceptors. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(44):18728–33. Epub 2009/10/24. doi: 10.1073/pnas.0902593106 19850870; PubMed Central PMCID: PMC2765920.
37. Lewis GP, Fisher SK. Up-regulation of glial fibrillary acidic protein in response to retinal injury: its potential role in glial remodeling and a comparison to vimentin expression. International review of cytology. 2003;230:264–90.
38. Roux KJ, Kim DI, Raida M, Burke B. A promiscuous biotin ligase fusion protein identifies proximal and interacting proteins in mammalian cells. The Journal of cell biology. 2012;196(6):801–10. Epub 2012/03/14. doi: 10.1083/jcb.201112098 22412018; PubMed Central PMCID: PMC3308701.
39. Bujalka H, Koenning M, Jackson S, Perreau VM, Pope B, Hay CM, et al. MYRF is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes. PLoS biology. 2013;11(8):e1001625. Epub 2013/08/24. doi: 10.1371/journal.pbio.1001625 23966833; PubMed Central PMCID: PMC3742440.
40. Emery B, Agalliu D, Cahoy JD, Watkins TA, Dugas JC, Mulinyawe SB, et al. Myelin gene regulatory factor is a critical transcriptional regulator required for CNS myelination. Cell. 2009;138(1):172–85. Epub 2009/07/15. doi: 10.1016/j.cell.2009.04.031 19596243; PubMed Central PMCID: PMC2757090.
41. Li Z, Park Y, Marcotte EM. A Bacteriophage tailspike domain promotes self-cleavage of a human membrane-bound transcription factor, the myelin regulatory factor MYRF. PLoS biology. 2013;11(8):e1001624. Epub 2013/08/24. doi: 10.1371/journal.pbio.1001624 23966832; PubMed Central PMCID: PMC3742443.
42. Kim D, Choi JO, Fan C, Shearer RS, Sharif M, Busch P, et al. Homo-trimerization is essential for the transcription factor function of Myrf for oligodendrocyte differentiation. Nucleic acids research. 2017;45(9):5112–25. Epub 2017/02/06. doi: 10.1093/nar/gkx080 28160598; PubMed Central PMCID: PMC5436001.
43. Liao X, Lan C, Liao D, Tian J, Huang X. Exploration and detection of potential regulatory variants in refractive error GWAS. Sci Rep. 2016;6:33090. Epub 2016/09/09. doi: 10.1038/srep33090 27604318; PubMed Central PMCID: PMC5015044.
44. Rymer J, Wildsoet CF. The role of the retinal pigment epithelium in eye growth regulation and myopia: a review. Visual neuroscience. 2005;22(3):251–61. Epub 2005/08/05. doi: 10.1017/S0952523805223015 16079001.
45. Dakubo GD, Mazerolle C, Furimsky M, Yu C, St-Jacques B, McMahon AP, et al. Indian hedgehog signaling from endothelial cells is required for sclera and retinal pigment epithelium development in the mouse eye. Developmental biology. 2008;320(1):242–55. Epub 2008/06/28. doi: 10.1016/j.ydbio.2008.05.528 18582859.
46. Zhang Y, Wildsoet CF. RPE and Choroid Mechanisms Underlying Ocular Growth and Myopia. Progress in molecular biology and translational science. 2015;134:221–40. Epub 2015/08/28. doi: 10.1016/bs.pmbts.2015.06.014 26310157; PubMed Central PMCID: PMC4755498.
47. Harper AR, Summers JA. The dynamic sclera: extracellular matrix remodeling in normal ocular growth and myopia development. Experimental eye research. 2015;133:100–11. Epub 2015/03/31. doi: 10.1016/j.exer.2014.07.015 25819458; PubMed Central PMCID: PMC4379420.
48. Gu SM, Thompson DA, Srikumari CR, Lorenz B, Finckh U, Nicoletti A, et al. Mutations in RPE65 cause autosomal recessive childhood-onset severe retinal dystrophy. Nat Genet. 1997;17(2):194–7. Epub 1997/11/05. doi: 10.1038/ng1097-194 9326941.
49. Morimura H, Fishman GA, Grover SA, Fulton AB, Berson EL, Dryja TP. Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis. Proceedings of the National Academy of Sciences of the United States of America. 1998;95(6):3088–93. Epub 1998/04/18. doi: 10.1073/pnas.95.6.3088 9501220; PubMed Central PMCID: PMC19699.
50. Hayward C, Shu X, Cideciyan AV, Lennon A, Barran P, Zareparsi S, et al. Mutation in a short-chain collagen gene, CTRP5, results in extracellular deposit formation in late-onset retinal degeneration: a genetic model for age-related macular degeneration. Human molecular genetics. 2003;12(20):2657–67. Epub 2003/08/29. doi: 10.1093/hmg/ddg289 12944416.
51. Gal A, Rau I, El Matri L, Kreienkamp H-J, Fehr S, Baklouti K, et al. Autosomal-recessive posterior microphthalmos is caused by mutations in PRSS56, a gene encoding a trypsin-like serine protease. The American Journal of Human Genetics. 2011;88(3):382–90. doi: 10.1016/j.ajhg.2011.02.006 21397065
52. Orr A, Dubé M-P, Zenteno JC, Jiang H, Asselin G, Evans SC, et al. Mutations in a novel serine protease PRSS56 in families with nanophthalmos. Molecular vision. 2011;17:1850. 21850159
53. Huang H, Teng P, Du J, Meng J, Hu X, Tang T, et al. Interactive repression of MYRF self-cleavage and activity in oligodendrocyte differentiation by TMEM98 protein. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2018. Epub 2018/09/27. doi: 10.1523/jneurosci.0154-18.2018 30249802.
54. Thaung C, West K, Clark BJ, McKie L, Morgan JE, Arnold K, et al. Novel ENU-induced eye mutations in the mouse: models for human eye disease. Human molecular genetics. 2002;11(7):755–67. Epub 2002/04/04. doi: 10.1093/hmg/11.7.755 11929848.
55. White JK, Gerdin A-K, Karp NA, Ryder E, Buljan M, Bussell JN, et al. Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes. Cell. 2013;154(2):452–64. doi: 10.1016/j.cell.2013.06.022 23870131
56. Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, et al. A conditional knockout resource for the genome-wide study of mouse gene function. Nature. 2011;474(7351):337. doi: 10.1038/nature10163 21677750
57. Wallace HA, Marques-Kranc F, Richardson M, Luna-Crespo F, Sharpe JA, Hughes J, et al. Manipulating the mouse genome to engineer precise functional syntenic replacements with human sequence. Cell. 2007;128(1):197–209. Epub 2007/01/16. doi: 10.1016/j.cell.2006.11.044 17218265.
58. Kleinjan DA, Seawright A, Mella S, Carr CB, Tyas DA, Simpson TI, et al. Long-range downstream enhancers are essential for Pax6 expression. Developmental biology. 2006;299(2):563–81. Epub 2006/10/04. doi: 10.1016/j.ydbio.2006.08.060 17014839; PubMed Central PMCID: PMC2386664.
59. Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, et al. Fiji: an open-source platform for biological-image analysis. Nature methods. 2012;9(7):676–82. Epub 2012/06/30. doi: 10.1038/nmeth.2019 22743772; PubMed Central PMCID: PMC3855844.
60. Jadeja S, Barnard AR, McKie L, Cross SH, White JK, Robertson M, et al. Mouse slc9a8 mutants exhibit retinal defects due to retinal pigmented epithelium dysfunction. Investigative ophthalmology & visual science. 2015;56(5):3015–26. Epub 2015/03/05. doi: 10.1167/iovs.14-15735 25736793; PubMed Central PMCID: PMC4538965.
61. Kammers K, Cole RN, Tiengwe C, Ruczinski I. Detecting Significant Changes in Protein Abundance. EuPA open proteomics. 2015;7:11–9. Epub 2015/03/31. doi: 10.1016/j.euprot.2015.02.002 25821719; PubMed Central PMCID: PMC4373093.
62. Perez-Riverol Y, Csordas A, Bai J, Bernal-Llinares M, Hewapathirana S, Kundu DJ, et al. The PRIDE database and related tools and resources in 2019: improving support for quantification data. Nucleic acids research. 2019;47(D1):D442–d50. Epub 2018/11/06. doi: 10.1093/nar/gky1106 30395289; PubMed Central PMCID: PMC6323896.
63. Hornig J, Frob F, Vogl MR, Hermans-Borgmeyer I, Tamm ER, Wegner M. The transcription factors Sox10 and Myrf define an essential regulatory network module in differentiating oligodendrocytes. PLoS Genet. 2013;9(10):e1003907. Epub 2013/11/10. doi: 10.1371/journal.pgen.1003907 24204311; PubMed Central PMCID: PMC3814293.
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