The purpose of the study is to demonstrate coherent optical tomography and electroretinography techniques adopted from the human clinical practice to assess the morphology and function of the mouse retina in a high-throughput phenotyping environment. We present the normal range of wild-type C57Bl/6NCrl retinal parameters in six age groups between 10 and 100 weeks as well as examples of mild and severe pathologies resulting from knocking out a single protein-coding gene. We also show example data obtained by more detailed analysis or additional methods useful in eye research, for example, the angiography of a superficial and deep vascular complex. We discuss the feasibility of these techniques in conditions demanding a high-throughput approach such as the systemic phenotyping carried out by the International Mouse Phenotyping Consortium.

Czech Centre for Phenogenomics Institute of Molecular Genetics Czech Academy of Sciences 252 50 Vestec Czech Republic

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Mouse Genome Sequencing C., Waterston R.H., Lindblad-Toh K., Birney E., Rogers J., Abril J.F., Agarwal P., Agarwala R., Ainscough R., Alexandersson M., et al. Initial sequencing and comparative analysis of the mouse genome. Nature. 2002;420:520–562. doi: 10.1038/nature01262. PubMed DOI

Antony B.J., Kim B.J., Lang A., Carass A., Prince J.L., Zack D.J. Automated segmentation of mouse OCT volumes (ASiMOV): Validation & clinical study of a light damage model. PLoS ONE. 2017;12:e0181059. doi: 10.1371/journal.pone.0181059. PubMed DOI PMC

Fischer M.D., Huber G., Beck S.C., Tanimoto N., Muehlfriedel R., Fahl E., Grimm C., Wenzel A., Reme C.E., van de Pavert S.A., et al. Noninvasive, in vivo assessment of mouse retinal structure using optical coherence tomography. PLoS ONE. 2009;4:e7507. doi: 10.1371/journal.pone.0007507. PubMed DOI PMC

Giannakaki-Zimmermann H., Kokona D., Wolf S., Ebneter A., Zinkernagel M.S. Optical Coherence Tomography Angiography in Mice: Comparison with Confocal Scanning Laser Microscopy and Fluorescein Angiography. Transl. Vis. Sci. Technol. 2016;5:11. doi: 10.1167/tvst.5.4.11. PubMed DOI PMC

Huber G., Beck S.C., Grimm C., Sahaboglu-Tekgoz A., Paquet-Durand F., Wenzel A., Humphries P., Redmond T.M., Seeliger M.W., Fischer M.D. Spectral domain optical coherence tomography in mouse models of retinal degeneration. Investig. Ophthalmol. Vis. Sci. 2009;50:5888–5895. doi: 10.1167/iovs.09-3724. PubMed DOI PMC

Ochakovski G.A., Fischer M.D. Phenotyping of Mouse Models with OCT. Methods Mol. Biol. 2019;1834:285–291. doi: 10.1007/978-1-4939-8669-9_18. PubMed DOI

Frishman L.J., Wang M.H. Adler’s Physiology of the Eye. Elsevier; Amsterdam, The Netherlands: 2011. Electroretinogram of Human, Monkey and Mouse.

Perlman I. The Electroretinogram: ERG by Ido Perlman. [(accessed on 24 October 2022)]. Available online: https://webvision.med.utah.edu/book/electrophysiology/the-electroretinogram-erg/

Penn R.D., Hagins W.A. Signal transmission along retinal rods and the origin of the electroretinographic a-wave. Nature. 1969;223:201–204. doi: 10.1038/223201a0. PubMed DOI

Green D.G., Kapousta-Bruneau N.V. A dissection of the electroretinogram from the isolated rat retina with microelectrodes and drugs. Vis. Neurosci. 1999;16:727–741. doi: 10.1017/S0952523899164125. PubMed DOI

Moore B.A., Leonard B.C., Sebbag L., Edwards S.G., Cooper A., Imai D.M., Straiton E., Santos L., Reilly C., Griffey S.M., et al. Identification of genes required for eye development by high-throughput screening of mouse knockouts. Commun. Biol. 2018;1:236. doi: 10.1038/s42003-018-0226-0. PubMed DOI PMC

Peachey N.S., Ball S.L. Electrophysiological analysis of visual function in mutant mice. Doc. Ophthalmol. 2003;107:13–36. doi: 10.1023/A:1024448314608. PubMed DOI

Schmucker C., Schaeffel F. In vivo biometry in the mouse eye with low coherence interferometry. Vis. Res. 2004;44:2445–2456. doi: 10.1016/j.visres.2004.05.018. PubMed DOI

Schmucker C., Schaeffel F. A paraxial schematic eye model for the growing C57BL/6 mouse. Vis. Res. 2004;44:1857–1867. doi: 10.1016/j.visres.2004.03.011. PubMed DOI

Moore B.A., Roux M.J., Sebbag L., Cooper A., Edwards S.G., Leonard B.C., Imai D.M., Griffey S., Bower L., Clary D., et al. A Population Study of Common Ocular Abnormalities in C57BL/6N rd8 Mice. Investig. Ophthalmol. Vis. Sci. 2018;59:2252–2261. doi: 10.1167/iovs.17-23513. PubMed DOI PMC

Jacobs G.H., Neitz J., Deegan J.F. Retinal receptors in rodents maximally sensitive to ultraviolet light. Nature. 1991;353:655–656. doi: 10.1038/353655a0. PubMed DOI

Calderone J.B., Jacobs G.H. Regional variations in the relative sensitivity to UV light in the mouse retina. Vis. Neurosci. 1995;12:463–468. doi: 10.1017/S0952523800008361. PubMed DOI

Jeon C.J., Strettoi E., Masland R.H. The major cell populations of the mouse retina. J. Neurosci. 1998;18:8936–8946. doi: 10.1523/JNEUROSCI.18-21-08936.1998. PubMed DOI PMC

Kostic C., Arsenijevic Y. Animal modelling for inherited central vision loss. J. Pathol. 2016;238:300–310. doi: 10.1002/path.4641. PubMed DOI PMC

Frishman L., Sustar M., Kremers J., McAnany J.J., Sarossy M., Tzekov R., Viswanathan S. ISCEV extended protocol for the photopic negative response (PhNR) of the full-field electroretinogram. Doc. Ophthalmol. 2018;136:207–211. doi: 10.1007/s10633-018-9638-x. PubMed DOI PMC

Johnson M.A., Jeffrey B.G., Messias A.M.V., Robson A.G. ISCEV extended protocol for the stimulus-response series for the dark-adapted full-field ERG b-wave. Doc. Ophthalmol. 2019;138:217–227. doi: 10.1007/s10633-019-09687-6. PubMed DOI PMC

McCulloch D.L., Kondo M., Hamilton R., Lachapelle P., Messias A.M.V., Robson A.G., Ueno S. ISCEV extended protocol for the stimulus-response series for light-adapted full-field ERG. Doc. Ophthalmol. 2019;138:205–215. doi: 10.1007/s10633-019-09685-8. PubMed DOI

McCulloch D.L., Marmor M.F., Brigell M.G., Hamilton R., Holder G.E., Tzekov R., Bach M. ISCEV Standard for full-field clinical electroretinography (2015 update) Doc. Ophthalmol. 2015;130:1–12. doi: 10.1007/s10633-014-9473-7. PubMed DOI

Sustar M., Holder G.E., Kremers J., Barnes C.S., Lei B., Khan N.W., Robson A.G. ISCEV extended protocol for the photopic On-Off ERG. Doc. Ophthalmol. 2018;136:199–206. doi: 10.1007/s10633-018-9645-y. PubMed DOI PMC

Lee I.N., Yang J.T., Huang C., Huang H.C., Wu Y.P., Chen J.C. Elevated XRCC5 expression level can promote temozolomide resistance and predict poor prognosis in glioblastoma. Oncol. Lett. 2021;21:443. doi: 10.3892/ol.2021.12704. PubMed DOI PMC

Savva C., Sadiq M., Sheikh O., Karim S., Trivedi S., Green A.R., Rakha E.A., Madhusudan S., Arora A. Werner Syndrome Protein Expression in Breast Cancer. Clin. Breast Cancer. 2021;21:57–73.e57. doi: 10.1016/j.clbc.2020.07.013. PubMed DOI

Shang B., Jia Y., Chen G., Wang Z. Ku80 correlates with neoadjuvant chemotherapy resistance in human lung adenocarcinoma, but reduces cisplatin/pemetrexed-induced apoptosis in A549 cells. Respir. Res. 2017;18:56. doi: 10.1186/s12931-017-0545-6. PubMed DOI PMC

Oshitari T., Kitahashi M., Mizuno S., Baba T., Kubota-Taniai M., Takemoto M., Yokote K., Yamamoto S., Roy S. Werner syndrome with refractory cystoid macular edema and immunohistochemical analysis of WRN proteins in human retinas. BMC Ophthalmol. 2014;14:31. doi: 10.1186/1471-2415-14-31. PubMed DOI PMC

Muller B., Serafin F., Laucke L.L., Rheinhard W., Wimmer T., Stieger K. Characterization of Double-Strand Break Repair Protein Ku80 Location Within the Murine Retina. Investig. Ophthalmol. Vis. Sci. 2022;63:22. doi: 10.1167/iovs.63.6.22. PubMed DOI PMC

Furukawa T., Morrow E.M., Li T., Davis F.C., Cepko C.L. Retinopathy and attenuated circadian entrainment in Crx-deficient mice. Nat. Genet. 1999;23:466–470. doi: 10.1038/70591. PubMed DOI

Berger W., Kloeckener-Gruissem B., Neidhardt J. The molecular basis of human retinal and vitreoretinal diseases. Prog. Retin. Eye Res. 2010;29:335–375. doi: 10.1016/j.preteyeres.2010.03.004. PubMed DOI

Tran N.M., Chen S. Mechanisms of blindness: Animal models provide insight into distinct CRX-associated retinopathies. Dev. Dyn. 2014;243:1153–1166. doi: 10.1002/dvdy.24151. PubMed DOI PMC

Gresh J., Goletz P.W., Crouch R.K., Rohrer B. Structure-function analysis of rods and cones in juvenile, adult, and aged C57bl/6 and Balb/c mice. Vis. Neurosci. 2003;20:211–220. doi: 10.1017/S0952523803202108. PubMed DOI

Wang Y., Grenell A., Zhong F., Yam M., Hauer A., Gregor E., Zhu S., Lohner D., Zhu J., Du J. Metabolic signature of the aging eye in mice. Neurobiol. Aging. 2018;71:223–233. doi: 10.1016/j.neurobiolaging.2018.07.024. PubMed DOI PMC

Tsantilas K.A., Cleghorn W.M., Bisbach C.M., Whitson J.A., Hass D.T., Robbings B.M., Sadilek M., Linton J.D., Rountree A.M., Valencia A.P., et al. An Analysis of Metabolic Changes in the Retina and Retinal Pigment Epithelium of Aging Mice. Investig. Ophthalmol. Vis. Sci. 2021;62:20. doi: 10.1167/iovs.62.14.20. PubMed DOI PMC

Kolesnikov A.V., Fan J., Crouch R.K., Kefalov V.J. Age-related deterioration of rod vision in mice. J. Neurosci. 2010;30:11222–11231. doi: 10.1523/JNEUROSCI.4239-09.2010. PubMed DOI PMC

Salobrar-Garcia E., Lopez-Cuenca I., Sanchez-Puebla L., de Hoz R., Fernandez-Albarral J.A., Ramirez A.I., Bravo-Ferrer I., Medina V., Moro M.A., Saido T.C., et al. Retinal Thickness Changes Over Time in a Murine AD Model APP (NL-F/NL-F) Front. Aging Neurosci. 2020;12:625642. doi: 10.3389/fnagi.2020.625642. PubMed DOI PMC

Ferdous S., Liao K.L., Gefke I.D., Summers V.R., Wu W., Donaldson K.J., Kim Y.K., Sellers J.T., Dixon J.A., Shelton D.A., et al. Age-Related Retinal Changes in Wild-Type C57BL/6J Mice Between 2 and 32 Months. Investig. Ophthalmol. Vis. Sci. 2021;62:9. doi: 10.1167/iovs.62.7.9. PubMed DOI PMC

Dysli C., Enzmann V., Sznitman R., Zinkernagel M.S. Quantitative Analysis of Mouse Retinal Layers Using Automated Segmentation of Spectral Domain Optical Coherence Tomography Images. Transl. Vis. Sci. Technol. 2015;4:9. doi: 10.1167/tvst.4.4.9. PubMed DOI PMC

Mattapallil M.J., Wawrousek E.F., Chan C.C., Zhao H., Roychoudhury J., Ferguson T.A., Caspi R.R. The Rd8 mutation of the Crb1 gene is present in vendor lines of C57BL/6N mice and embryonic stem cells, and confounds ocular induced mutant phenotypes. Investig. Ophthalmol. Vis. Sci. 2012;53:2921–2927. doi: 10.1167/iovs.12-9662. PubMed DOI PMC

Moshiri A. Animals Models of Inherited Retinal Disease. Int. Ophthalmol. Clin. 2021;61:113–130. doi: 10.1097/IIO.0000000000000368. PubMed DOI PMC

Aleman T.S., Cideciyan A.V., Aguirre G.K., Huang W.C., Mullins C.L., Roman A.J., Sumaroka A., Olivares M.B., Tsai F.F., Schwartz S.B., et al. Human CRB1-associated retinal degeneration: Comparison with the rd8 Crb1-mutant mouse model. Investig. Ophthalmol. Vis. Sci. 2011;52:6898–6910. doi: 10.1167/iovs.11-7701. PubMed DOI PMC

Saul A.B., Cui X., Markand S., Smith S.B. Detailed electroretinographic findings in rd8 mice. Doc. Ophthalmol. 2017;134:195–203. doi: 10.1007/s10633-017-9585-y. PubMed DOI

Rosch S., Johnen S., Muller F., Pfarrer C., Walter P. Correlations between ERG, OCT, and Anatomical Findings in the rd10 Mouse. J. Ophthalmol. 2014;2014:874751. doi: 10.1155/2014/874751. PubMed DOI PMC

Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver