Hostname: page-component-78c5997874-dh8gc Total loading time: 0 Render date: 2024-11-16T17:11:30.291Z Has data issue: false hasContentIssue false
  • English
  • Français

Myelin regulatory factor deficiency is associated with the retinal photoreceptor defects in mice

Published online by Cambridge University Press:  03 May 2021

Xiaowei Yu ,
Nannan Sun ,
Xue Yang ,
Zhenni Zhao ,
Jiamin Zhang ,
Miao Zhang ,
Dandan Zhang ,
Jian Ge  and
Zhigang Fan Open the ORCID record for Zhigang Fan [Opens in a new window]
Xiaowei Yu
Affiliation:
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
Nannan Sun
Affiliation:
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
Xue Yang
Affiliation:
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
Zhenni Zhao
Affiliation:
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
Jiamin Zhang
Affiliation:
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
Miao Zhang
Affiliation:
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
Dandan Zhang
Affiliation:
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
Jian Ge*
Affiliation:
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
Zhigang Fan*
Affiliation:
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing, China
*
Jian Ge, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, No. 7, Jinsui Road, Guangzhou, 510060, China. Email: [email protected]
Address correspondence to: Zhigang Fan, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, No. 7, Jinsui Road, Guangzhou510060, China. Email: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Previously, we reported the myelin regulatory factor (MYRF) as a candidate gene for nanophthalmos. We have also produced Myrf knockdown (Myrf+/−) mouse strain to investigate the cellular and molecular phenotypes of reduced MYRF expression in the retina. Myrf+/− mouse strain was generated using the CRISPR/Cas9 system. Optomotor response system, electroretinogram (ERG), spectral-domain optical coherence tomography (SD-OCT), histology, and immunohistochemistry were performed to evaluate retinal spatial vision, electrophysiological function, retinal thickness, and pathological changes in cone or rod photoreceptors, respectively. RNA sequencing (RNA-seq) was performed to investigate the underlying molecular mechanism linking Myrf deficiency with photoreceptor defects. The genotype and phenotype of CRISPR/Cas9-induced Myrf+/− mice and their offspring were comprehensively investigated. Photoreceptor defects were detected in the retinas of Myrf+/− mice. Visual acuity and ERG responses were decreased in Myrf+/− mice compared with the control mice (Myrf+/+). The loss of cone and rod neurons was proportional to the decreased outer nuclear layer (ONL) thickness. Moreover, RNA-seq revealed that phototransduction and estrogen signaling pathways played important roles in the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Myrf+/− mouse strain provides a good model to investigate the function of the MYRF gene. Photoreceptor defects with impaired functions of spatial vision and retinal electrophysiology indicate an important role played by MYRF in retinal development. Alterations in phototransduction and estrogen signaling pathways play important roles in linking Myrf deficiency with retinal photoreceptor defects.

Keywords

nanophthalmosMyrf knockdown miceretinal developmentphotoreceptor defectsRNA sequencing
Type
Research Article
Information
Visual Neuroscience , Volume 38 , 2021 , E005
Check for updates
Copyright
© The Author(s), 2021. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Albar, A.A., Nowilaty, S.R. & Ghazi, N.G. (2015). Nanophthalmos and hemiretinal vein occlusion: A case report. Saudi Journal of Ophthalmology: Official Journal of the Saudi Ophthalmological Society 29, 89–91.CrossRefGoogle ScholarPubMed
Bao, J., Ma, H.-Y., Schuster, A., Lin, Y.-M. & Yan, W. (2013). Incomplete cre-mediated excision leads to phenotypic differences between Stra8-iCre; Mov10l1lox/lox and Stra8-iCre; Mov10l1lox/Δ mice. Genesis (New York, NY: 2000) 51, 481–490.CrossRefGoogle ScholarPubMed
Barabas, P., Huang, W., Chen, H., Koehler, C.L., Howell, G., John, S.W.M., Tian, N., Rentería, R.C. & Krizaj, D. (2011). Missing optomotor head-turning reflex in the DBA/2J mouse. Investigative Ophthalmology & Visual Science 52, 6766–6773.CrossRefGoogle ScholarPubMed
Carricondo, P.C., Andrade, T., Prasov, L., Ayres, B.M. & Moroi, S.E. (2018). Nanophthalmos: A review of the clinical spectrum and genetics. Journal of Ophthalmology 2018, 2735465.CrossRefGoogle ScholarPubMed
Cascio, C., Russo, D., Drago, G., Galizzi, G., Passantino, R., Guarneri, R. & Guarneri, P. (2007). 17beta-Estradiol synthesis in the adult male rat retina. Experimental Eye Research 85, 166–172.CrossRefGoogle ScholarPubMed
Crespí, J., Buil, J.A., Bassaganyas, F., Vela-Segarra, J.I., Díaz-Cascajosa, J., Ayala-Ramírez, R. & Zenteno, J.C. (2008). A novel mutation confirms MFRP as the gene causing the syndrome of nanophthalmos-renititis pigmentosa-foveoschisis-optic disk drusen. American Journal of Ophthalmology 146, 323–328.CrossRefGoogle ScholarPubMed
Cross, S.H., McKie, L., Keighren, M., West, K., Thaung, C., Davey, T., Soares, D.C., Sanchez-Pulido, L. & Jackson, I.J. (2019). Missense mutations in the human nanophthalmos gene TMEM98 cause retinal defects in the mouse. Investigative Ophthalmology & Visual Science 60, 2875–2887.CrossRefGoogle ScholarPubMed
Emery, B., Agalliu, D., Cahoy, J.D., Watkins, T.A., Dugas, J.C., Mulinyawe, S.B., Ibrahim, A., Ligon, K.L., Rowitch, D.H. & Barres, B.A. (2009). Myelin gene regulatory factor is a critical transcriptional regulator required for CNS myelination. Cell 138, 172–185.CrossRefGoogle ScholarPubMed
Fogerty, J. & Besharse, J.C. (2011). 174delG mutation in mouse MFRP causes photoreceptor degeneration and RPE atrophy. Investigative Ophthalmology & Visual Science 52, 7256–7266.CrossRefGoogle ScholarPubMed
Friesen, C.N., Ramsey, M.E. & Cummings, M.E. (2017). Differential sensitivity to estrogen-induced opsin expression in two poeciliid freshwater fish species. General and Comparative Endocrinology 246, 200–210.CrossRefGoogle ScholarPubMed
Garnai, S.J., Brinkmeier, M.L., Emery, B., Aleman, T.S., Pyle, L.C., Veleva-Rotse, B., Sisk, R.A., Rozsa, F.W., Ozel, A.B., Li, J.Z., Moroi, S.E., Archer, S.M., Lin, C.-M., Sheskey, S., Wiinikka-Buesser, L., Eadie, J., Urquhart, J.E., Black, G.C.M., Othman, M.I., Boehnke, M., Sullivan, S.A., Skuta, G.L., Pawar, H.S., Katz, A.E., Huryn, L.A., Hufnagel, R.B., Camper, S.A., Richards, J.E. & Prasov, L. (2019). Variants in myelin regulatory factor (MYRF) cause autosomal dominant and syndromic nanophthalmos in humans and retinal degeneration in mice. PLoS Genetics 15, e1008130.CrossRefGoogle ScholarPubMed
Guo, C., Zhao, Z., Chen, D., He, S., Sun, N., Li, Z., Liu, J., Zhang, D., Zhang, J., Li, J., Zhang, M., Ge, J., Liu, X., Zhang, X. & Fan, Z. (2019a). Detection of clinically relevant genetic variants in Chinese patients with nanophthalmos by trio-based whole-genome sequencing study. Investigative Ophthalmology & Visual Science 60, 2904–2913.CrossRefGoogle Scholar
Guo, C., Zhao, Z., Zhang, D., Liu, J., Li, J., Zhang, J., Sun, N., Chen, D., Zhang, M. & Fan, Z. (2019b). Anterior segment features in nanophthalmos with secondary chronic angle closure glaucoma: An ultrasound biomicroscopy study. Investigative Ophthalmology & Visual Science 60, 2248–2256.CrossRefGoogle Scholar
Hirahara, Y., Matsuda, K.I., Liu, Y.F., Yamada, H., Kawata, M. & Boggs, J.M. (2013). 17beta-Estradiol and 17alpha-estradiol induce rapid changes in cytoskeletal organization in cultured oligodendrocytes. Neuroscience 235, 187–199.CrossRefGoogle ScholarPubMed
Kameya, S., Hawes, N.L., Chang, B., Heckenlively, J.R., Naggert, J.K. & Nishina, P.M. (2002). Mfrp, a gene encoding a frizzled related protein, is mutated in the mouse retinal degeneration 6. Human Molecular Genetics 11, 1879–1886.CrossRefGoogle ScholarPubMed
Kretschmer, F., Sajgo, S., Kretschmer, V. & Badea, T.C. (2015). A system to measure the optokinetic and optomotor response in mice. Journal of Neuroscience Methods 256.CrossRefGoogle ScholarPubMed
Kumar, D.M., Simpkins, J.W. & Agarwal, N. (2008). Estrogens and neuroprotection in retinal diseases. Molecular Vision 14, 1480–1486.Google ScholarPubMed
MacKay, C.J., Shek, M.S., Carr, R.E., Yanuzzi, L.A. & Gouras, P. (1987). Retinal degeneration with nanophthalmos, cystic macular degeneration, and angle closure glaucoma. A new recessive syndrome. Archives of Ophthalmology (Chicago, IL: 1960) 105, 366–371.CrossRefGoogle ScholarPubMed
Marin, R., Guerra, B., Alonso, R., Ramirez, C.M. & Diaz, M. (2005). Estrogen activates classical and alternative mechanisms to orchestrate neuroprotection. Current Neurovascular Research 2, 287–301.CrossRefGoogle ScholarPubMed
Mehalow, A.K., Kameya, S., Smith, R.S., Hawes, N.L., Denegre, J.M., Young, J.A., Bechtold, L., Haider, N.B., Tepass, U., Heckenlively, J.R., Chang, B., Naggert, J.K. & Nishina, P.M. (2003). CRB1 is essential for external limiting membrane integrity and photoreceptor morphogenesis in the mammalian retina. Human Molecular Genetics 12, 2179–2189.CrossRefGoogle ScholarPubMed
Nair, K.S., Hmani-Aifa, M., Ali, Z., Kearney, A.L., Ben Salem, S., Macalinao, D.G., Cosma, I.M., Bouassida, W., Hakim, B., Benzina, Z., Soto, I., Soderkvist, P., Howell, G.R., Smith, R.S., Ayadi, H. & John, S.W. (2011). Alteration of the serine protease PRSS56 causes angle-closure glaucoma in mice and posterior microphthalmia in humans and mice. Nature Genetics 43, 579–584.CrossRefGoogle ScholarPubMed
O’Neill, E.E., Blewett, A.R., Loria, P.M. & Greene, G.L. (2008). Modulation of alphaCaMKII signaling by rapid ERalpha action. Brain Research 1222, 1–17.CrossRefGoogle ScholarPubMed
Orr, A., Dube, M.P., Zenteno, J.C., Jiang, H., Asselin, G., Evans, S.C., Caqueret, A., Lakosha, H., Letourneau, L., Marcadier, J., Matsuoka, M., Macgillivray, C., Nightingale, M., Papillon-Cavanagh, S., Perry, S., Provost, S., Ludman, M., Guernsey, D.L. & Samuels, M.E. (2011). Mutations in a novel serine protease PRSS56 in families with nanophthalmos. Molecular Vision 17, 1850–1861.Google Scholar
Paun, C.C., Pijl, B.J., Siemiatkowska, A.M., Collin, R.W., Cremers, F.P., Hoyng, C.B. & den Hollander, A.I. (2012). A novel crumbs homolog 1 mutation in a family with retinitis pigmentosa, nanophthalmos, and optic disc drusen. Molecular Vision 18, 2447–2453.Google Scholar
Pertea, M., Pertea, G.M., Antonescu, C.M., Chang, T.C., Mendell, J.T., & Salzberg, S.L. (2015). StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nature Biotechnology 33, 290–295.CrossRefGoogle ScholarPubMed
Prusky, G.T., Alam, N.M., Beekman, S. & Douglas, R.M. (2004). Rapid quantification of adult and developing mouse spatial vision using a virtual optomotor system. Investigative Ophthalmology & Visual Science 45, 4611–4616.CrossRefGoogle ScholarPubMed
Robinson, M.D., McCarthy, D.J. & Smyth, G.K. (2010). edgeR: A bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics (Oxford, England) 26, 139–140.CrossRefGoogle ScholarPubMed
Rymer, J. & Wildsoet, C.F. (2005). The role of the retinal pigment epithelium in eye growth regulation and myopia: A review. Visual Neuroscience 22, 251–261.CrossRefGoogle ScholarPubMed
Sandlesh, P., Juang, T., Safina, A., Higgins, M.J. & Gurova, K.V. (2018). Uncovering the fine print of the CreERT2-LoxP system while generating a conditional knockout mouse model of Ssrp1 gene. PLoS One 13, e0199785.CrossRefGoogle ScholarPubMed
Schneider, C.A., Rasband, W.S. & Eliceiri, K.W. (2012). NIH image to ImageJ: 25 years of image analysis. Nature Methods 9, 671–675.CrossRefGoogle ScholarPubMed
Simpkins, J.W., Wen, Y., Perez, E., Yang, S. & Wang, X. (2005). Role of nonfeminizing estrogens in brain protection from cerebral ischemia: An animal model of Alzheimer’s disease neuropathology. Annals of the New York Academy of Sciences 1052, 233–242.CrossRefGoogle ScholarPubMed
Soundararajan, R., Won, J., Stearns, T.M., Charette, J.R., Hicks, W.L., Collin, G.B., Naggert, J.K., Krebs, M.P. & Nishina, P.M. (2014). Gene profiling of postnatal Mfrprd6 mutant eyes reveals differential accumulation of Prss56, visual cycle and phototransduction mRNAs. PLoS One 9, e110299.CrossRefGoogle ScholarPubMed
Thaung, C., West, K., Clark, B.J., McKie, L., Morgan, J.E., Arnold, K., Nolan, P.M., Peters, J., Hunter, A.J., Brown, S.D.M., Jackson, I.J. & Cross, S.H. (2002). Novel ENU-induced eye mutations in the mouse: Models for human eye disease. Human Molecular Genetics 11, 755–767.CrossRefGoogle ScholarPubMed
Tkatchenko, T.V., Troilo, D., Benavente-Perez, A. & Tkatchenko, A.V. (2018). Gene expression in response to optical defocus of opposite signs reveals bidirectional mechanism of visually guided eye growth. PLoS Biology 16, e2006021.CrossRefGoogle ScholarPubMed
Velez, G., Tsang, S.H., Tsai, Y.-T., Hsu, C.-W., Gore, A., Abdelhakim, A.H., Mahajan, M., Silverman, R.H., Sparrow, J.R., Bassuk, A.G. & Mahajan, V.B. (2017). Gene therapy restores Mfrp and corrects axial eye length. Scientific Reports 7, 16151.CrossRefGoogle ScholarPubMed
Verma, A.S. & Fitzpatrick, D.R. (2007). Anophthalmia and microphthalmia. Orphanet Journal of Rare Diseases 2, 47.CrossRefGoogle ScholarPubMed
Xiao, H., Guo, X., Zhong, Y. & Liu, X. (2015). Retinal and choroidal changes of nanophthalmic eyes with and without secondary glaucoma. Retina (Philadelphia, PA) 35, 2121–2129.CrossRefGoogle ScholarPubMed
Xiao, J., Adil, M.Y., Chang, K., Yu, Z., Yang, L., Utheim, T.P., Chen, D.F. & Cho, K.S. (2019). Visual Contrast Sensitivity Correlates to the Retinal Degeneration in Rhodopsin Knockout Mice. Investigative Ophthalmology & Visual Science 60, 4196–4204.CrossRefGoogle ScholarPubMed
Xiao, X., Sun, W., Ouyang, J., Li, S., Jia, X., Tan, Z., Hejtmancik, J.F. & Zhang, Q. (2019). Novel truncation mutations in MYRF cause autosomal dominant high hyperopia mapped to 11p12-q13.3. Human Genetics 138, 1077–1090.CrossRefGoogle ScholarPubMed
Yang, H., Wang, H. & Jaenisch, R. (2014). Generating genetically modified mice using CRISPR/Cas-mediated genome engineering. Nature Protocols 9, 1956–1968.CrossRefGoogle ScholarPubMed
Yardley, J, Leroy, B.P., Hart-Holden, N., Lafaut, B.A., Loeys, B., Messiaen, L.M., Perveen, R., Reddy, M.A., Bhattacharya, S.S., Traboulsi, E., Baralle, D., De Laey, J.-J., Puech, B., Kestelyn, P., Moore, A.T., Manson, F.D.C. & Black, G.C.M. (2004). Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC). Investigative Ophthalmology & Visual Science 45, 3683–3689.CrossRefGoogle Scholar
Yu, X., Sun, N., Yang, X., Zhao, Z., Su, X., Zhang, J., He, Y., Lin, Y., Ge, Y. & Fan, Z. (2021). Nanophthalmos-Associated MYRF Gene Mutation Causes Ciliary Zonule Defects in Mice. Investigative ophthalmology & visual science 62, 1.CrossRefGoogle ScholarPubMed
Zacharias, L.C., Susanna, R., Sundin, O., Finzi, S., Susanna, B.N. & Takahashi, W.Y. (2015). Efficacy of topical dorzolamide therapy for cystoid macular edema in a patient with MFRP-related nanophthalmos–retinitis pigmentosa–foveoschisis–optic disk drusen syndrome. Retinal Cases & Brief Reports 9, 61–63.CrossRefGoogle Scholar
Zenteno, J.C., Buentello-Volante, B., Ayala-Ramirez, R. & Villanueva-Mendoza, C. (2011). Homozygosity mapping identifies the Crumbs homologue 1 (Crb1) gene as responsible for a recessive syndrome of retinitis pigmentosa and nanophthalmos. The American Journal of Medical Genetics—Part A 155A, 1001–1006.CrossRefGoogle ScholarPubMed
Supplementary material: File

Yu et al. supplementary material

Yu et al. supplementary material

Download Yu et al. supplementary material(File)
File 20.5 KB