Identification of MFRP and the secreted serine proteases PRSS56 and ADAMTS19 as part of a molecular network involved in ocular growth regulation
Autoři:
Swanand Koli aff001; Cassandre Labelle-Dumais aff001; Yin Zhao aff001; Seyyedhassan Paylakhi aff001; K. Saidas Nair aff001
Působiště autorů:
Department of Ophthalmology, University of California, San Francisco, California, United States of America
aff001; Department of Anatomy, University of California, San Francisco, California, United States of America
aff002
Vyšlo v časopise:
Identification of MFRP and the secreted serine proteases PRSS56 and ADAMTS19 as part of a molecular network involved in ocular growth regulation. PLoS Genet 17(3): e1009458. doi:10.1371/journal.pgen.1009458
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1009458
Souhrn
Precise regulation of ocular size is a critical determinant of normal visual acuity. Although it is generally accepted that ocular growth relies on a cascade of signaling events transmitted from the retina to the sclera, the factors and mechanism(s) involved are poorly understood. Recent studies have highlighted the importance of the retinal secreted serine protease PRSS56 and transmembrane glycoprotein MFRP, a factor predominantly expressed in the retinal pigment epithelium (RPE), in ocular size determination. Mutations in PRSS56 and MFRP constitute a major cause of nanophthalmos, a condition characterized by severe reduction in ocular axial length/extreme hyperopia. Interestingly, common variants of these genes have been implicated in myopia, a condition associated with ocular elongation. Consistent with these findings, mice with loss of function mutation in PRSS56 or MFRP exhibit a reduction in ocular axial length. However, the molecular network and cellular processes involved in PRSS56- and MFRP-mediated ocular axial growth remain elusive. Here, we show that Adamts19 expression is significantly upregulated in the retina of mice lacking either Prss56 or Mfrp. Importantly, using genetic mouse models, we demonstrate that while ADAMTS19 is not required for ocular growth during normal development, its inactivation exacerbates ocular axial length reduction in Prss56 and Mfrp mutant mice. These results suggest that the upregulation of retinal Adamts19 is part of an adaptive molecular response to counteract impaired ocular growth. Using a complementary genetic approach, we show that loss of PRSS56 or MFRP function prevents excessive ocular axial growth in a mouse model of early-onset myopia caused by a null mutation in Irbp, thus, demonstrating that PRSS56 and MFRP are also required for pathological ocular elongation. Collectively, our findings provide new insights into the molecular network involved in ocular axial growth and support a role for molecular crosstalk between the retina and RPE involved in refractive development.
Klíčová slova:
Myopia – Biometrics – Eyes – Gene expression – Genetically modified animals – Genetics – Mouse models – Retina
Zdroje
1. Carricondo PC, Andrade T, Prasov L, Ayres BM, Moroi SE. Nanophthalmos: A Review of the Clinical Spectrum and Genetics. J Ophthalmol. 2018;2018:2735465. doi: 10.1155/2018/2735465 29862063; PubMed Central PMCID: PMC5971257.
2. Siggs OM, Awadalla MS, Souzeau E, Staffieri SE, Kearns LS, Laurie K, et al. The genetic and clinical landscape of nanophthalmos and posterior microphthalmos in an Australian cohort. Clin Genet. 2020;97(5):764–9. doi: 10.1111/cge.13722 32052405.
3. Nair KS, Hmani-Aifa M, Ali Z, Kearney AL, Ben Salem S, 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(6):579–84. Epub 2011/05/03. doi: 10.1038/ng.813 21532570.
4. Gal A, Rau I, El Matri L, Kreienkamp HJ, Fehr S, Baklouti K, et al. Autosomal-recessive posterior microphthalmos is caused by mutations in PRSS56, a gene encoding a trypsin-like serine protease. American journal of human genetics. 2011;88(3):382–90. Epub 2011/03/15. doi: 10.1016/j.ajhg.2011.02.006 21397065; PubMed Central PMCID: PMC3059417.
5. Orr A, Dube MP, Zenteno JC, Jiang H, Asselin G, Evans SC, et al. Mutations in a novel serine protease PRSS56 in families with nanophthalmos. Molecular vision. 2011;17:1850–61. Epub 2011/08/19. 21850159; PubMed Central PMCID: PMC3137557.
6. Sundin OH, Leppert GS, Silva ED, Yang J-M, Dharmaraj S, Maumenee IH, et al. Extreme hyperopia is the result of null mutations in MFRP, which encodes a Frizzled-related protein. Proceedings of the National Academy of Sciences of the United States of America. 2005;102(27):9553–8. Medline:15976030. doi: 10.1073/pnas.0501451102 15976030
7. 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 Ophthalmol. 2014;132(8):970–7. doi: 10.1001/jamaophthalmol.2014.946 24852644.
8. Cross SH, McKie L, Hurd TW, Riley S, Wills J, Barnard AR, et al. The nanophthalmos protein TMEM98 inhibits MYRF self-cleavage and is required for eye size specification. PLoS genetics. 2020;16(4):e1008583. doi: 10.1371/journal.pgen.1008583 32236127; PubMed Central PMCID: PMC7153906.
9. 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 genetics. 2019;15(5):e1008130. doi: 10.1371/journal.pgen.1008130 31048900; PubMed Central PMCID: PMC6527243.
10. Almoallem B, Arno G, De Zaeytijd J, Verdin H, Balikova I, Casteels I, et al. The majority of autosomal recessive nanophthalmos and posterior microphthalmia can be attributed to biallelic sequence and structural variants in MFRP and PRSS56. Sci Rep. 2020;10(1):1289. doi: 10.1038/s41598-019-57338-2 31992737; PubMed Central PMCID: PMC6987234.
11. 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. Nature genetics. 2018;50(6):834–+. doi: 10.1038/s41588-018-0127-7 WOS:000433621000011. 29808027
12. Hysi PG, Choquet H, Khawaja AP, Wojciechowski R, Tedja MS, Yin J, et al. Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia. Nature genetics. 2020;52(4):401–7. doi: 10.1038/s41588-020-0599-0 32231278; PubMed Central PMCID: PMC7145443.
13. 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 genetics. 2018;14(3):e1007244. doi: 10.1371/journal.pgen.1007244 29529029; PubMed Central PMCID: PMC5864079.
14. Collery RF, Volberding PJ, Bostrom JR, Link BA, Besharse JC. Loss of Zebrafish Mfrp Causes Nanophthalmia, Hyperopia, and Accumulation of Subretinal Macrophages. Investigative ophthalmology & visual science. 2016;57(15):6805–14. Epub 2016/12/22. doi: 10.1167/iovs.16-19593 28002843; PubMed Central PMCID: PMC5215506.
15. Fogerty J, Besharse JC. 174delG mutation in mouse MFRP causes photoreceptor degeneration and RPE atrophy. Investigative ophthalmology & visual science. 2011;52(10):7256–66. Medline:21810984. doi: 10.1167/iovs.11-8112 21810984
16. Velez G, Tsang SH, Tsai YT, Hsu CW, Gore A, Abdelhakim AH, et al. Gene Therapy Restores Mfrp and Corrects Axial Eye Length. Sci Rep. 2017;7(1):16151. doi: 10.1038/s41598-017-16275-8 29170418; PubMed Central PMCID: PMC5701072.
17. Siegwart JT Jr, Norton TT. Perspective: how might emmetropization and genetic factors produce myopia in normal eyes? Optometry and vision science: official publication of the American Academy of Optometry. 2011;88(3):E365–72. Medline:21258261. doi: 10.1097/OPX.0b013e31820b053d 21258261
18. Sundin OH, Dharmaraj S, Bhutto IA, Hasegawa T, McLeod DS, Merges CA, et al. Developmental basis of nanophthalmos: MFRP Is required for both prenatal ocular growth and postnatal emmetropization. Ophthalmic Genet. 2008;29(1):1–9. Medline:18363166. doi: 10.1080/13816810701651241 18363166
19. Stone RA, Pardue MT, Iuvone PM, Khurana TS. Pharmacology of myopia and potential role for intrinsic retinal circadian rhythms. Experimental eye research. 2013;114:35–47. Epub 2013/01/15. doi: 10.1016/j.exer.2013.01.001 23313151; PubMed Central PMCID: PMC3636148.
20. Pardue MT, Stone RA, Iuvone PM. Investigating mechanisms of myopia in mice. Experimental eye research. 2013;114:96–105. Epub 2013/01/12. doi: 10.1016/j.exer.2012.12.014 23305908; PubMed Central PMCID: PMC3898884.
21. Rymer J, Wildsoet CF. The role of the retinal pigment epithelium in eye growth regulation and myopia: a review. Vis Neurosci. 2005;22(3):251–61. Medline:16079001. doi: 10.1017/S0952523805223015 16079001
22. Soundararajan R, Won J, Stearns TM, Charette JR, Hicks WL, Collin GB, et al. Gene profiling of postnatal Mfrprd6 mutant eyes reveals differential accumulation of Prss56, visual cycle and phototransduction mRNAs. PloS one. 2014;9(10):e110299. Epub 2014/10/31. doi: 10.1371/journal.pone.0110299 25357075; PubMed Central PMCID: PMC4214712.
23. Wisard J, Faulkner A, Chrenek MA, Waxweiler T, Waxweiler W, Donmoyer C, et al. Exaggerated eye growth in IRBP-deficient mice in early development. Investigative ophthalmology & visual science. 2011;52(8):5804–11. Medline:21642628. doi: 10.1167/iovs.10-7129 21642628
24. Schippert R, Burkhardt E, Feldkaemper M, Schaeffel F. Relative axial myopia in Egr-1 (ZENK) knockout mice. Investigative ophthalmology & visual science. 2007;48(1):11–7. doi: 10.1167/iovs.06-0851 17197510.
25. 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. doi: 10.1167/iovs.18-25954 31266059; PubMed Central PMCID: PMC6986908.
26. 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. 10967077.
27. Bringmann A, Pannicke T, Grosche J, Francke M, Wiedemann P, Skatchkov SN, et al. Muller cells in the healthy and diseased retina. Progress in retinal and eye research. 2006;25(4):397–424. Epub 2006/07/15. doi: 10.1016/j.preteyeres.2006.05.003 16839797.
28. Lindqvist N, Liu Q, Zajadacz J, Franze K, Reichenbach A. Retinal glial (Muller) cells: sensing and responding to tissue stretch. Investigative ophthalmology & visual science. 2010;51(3):1683–90. Medline:19892866. doi: 10.1167/iovs.09-4159 19892866
29. Mammoto A, Mammoto T, Ingber DE. Mechanosensitive mechanisms in transcriptional regulation. J Cell Sci. 2012;125(Pt 13):3061–73. doi: 10.1242/jcs.093005 22797927; PubMed Central PMCID: PMC3434847.
30. Wang X, Xu GZ. Gene expression changes under cyclic mechanical stretching in rat retinal glial (Muller) cells. Investigative ophthalmology & visual science. 2013;54(15). WOS:000436232700284. doi: 10.1371/journal.pone.0063467 23723984
31. Uechi G, Sun Z, Schreiber EM, Halfter W, Balasubramani M. Proteomic View of Basement Membranes from Human Retinal Blood Vessels, Inner Limiting Membranes, and Lens Capsules. Journal of proteome research. 2014;13(8):3693–705. doi: 10.1021/pr5002065 24990792.
32. Halfter W, Winzen U, Bishop PN, Eller A. Regulation of eye size by the retinal basement membrane and vitreous body. Investigative ophthalmology & visual science. 2006;47(8):3586–94. doi: 10.1167/iovs.05-1480 16877433.
33. Smith SL, Trachtenberg JT. Experience-dependent binocular competition in the visual cortex begins at eye opening. Nature neuroscience. 2007;10(3):370–5. doi: 10.1038/nn1844 17293862.
34. Tkatchenko TV, Troilo D, Benavente-Perez A, Tkatchenko AV. Gene expression in response to optical defocus of opposite signs reveals bidirectional mechanism of visually guided eye growth. PLoS Biol. 2018;16(10):e2006021. doi: 10.1371/journal.pbio.2006021 30300342; PubMed Central PMCID: PMC6177118.
35. Fan Q, Pozarickij A, Tan NYQ, Guo X, Verhoeven VJM, Vitart V, et al. Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error. Commun Biol. 2020;3(1):133. doi: 10.1038/s42003-020-0802-y 32193507; PubMed Central PMCID: PMC7081241.
36. Jourdon A, Gresset A, Spassky N, Charnay P, Topilko P, Santos R. Prss56, a novel marker of adult neurogenesis in the mouse brain. Brain structure & function. 2016;221(9):4411–27. Epub 2015/12/25. doi: 10.1007/s00429-015-1171-z 26701169.
37. Lee SL, Tourtellotte LC, Wesselschmidt RL, Milbrandt J. Growth and differentiation proceeds normally in cells deficient in the immediate early gene NGFI-A. J Biol Chem. 1995;270(17):9971–7. doi: 10.1074/jbc.270.17.9971 7730380.
38. Wunnemann F, Ta-Shma A, Preuss C, Leclerc S, van Vliet PP, Oneglia A, et al. Loss of ADAMTS19 causes progressive non-syndromic heart valve disease. Nature genetics. 2020;52(1):40–7. Medline:31844321. doi: 10.1038/s41588-019-0536-2 31844321
39. 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. Medline:12915475. doi: 10.1093/hmg/ddg232 12915475
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