325 The Mouse Model of Myopia
Image processing and regulation of retinal genes and proteins
Studies on the regulation of the retinal mRNA of Egr-1 by light and retinal image contrast in mice showed surprisingly high sensitivity to the changes in retinal image contrast — despite their low acuity and large depth of field. Even if the retinal illumination was matched in the fellow eye by using neutral density filters that had similar light attentuation as the diffusers, the minor difference in image contrast had clear effects on Egr-1 mRNA concentrations in the retina.74 Furthermore, a microarray analysis of gene expression under the same visual stimulation conditions showed surprisingly clear transcription changes of a number of genes.75 This shows that even minor differences in image contrast were detected.
Beuerman et al.76 studied the role of transglutaminase 2 (TGM-2) during the development of lens-induced myopia in albino mice. They found a significant up-regulation of TGM-2 in the retina after eight weeks of treatment, which was fully suppressed by simultaneous atropine treatment.
More recently, Beuerman et al.77 studied retinal protein expression following –10 D lens wear in albino mice, which induced 10.5 D relative myopia and an axial elongation of 0.31 mm. From 200 identified proteins, 18 were significantly up-regulated and 10 were down-regulated. It is interesting that one of them was a Muller cell marker (Vementin). All proteins could be assigned to certain molecular and biological functions. It is clear that such studies may help in identifying potential targets for pharmacological intervention of myopia, and understanding the signalling cascades from retina to sclera.
Summary
Despite its lower spatial resolution than would be possible based on the size of the eye, inferior optics, and slow eye growth, the mouse seems on its way to becoming an important model for studies on myopia. The required technology to induce and measure experimentally induced refractive errors is now available, and highly significant changes in those variables could be induced by diffusers and eyeglass lens wear. Knock-out models, lacking presumed elements of the signalling cascade translating the output of retinal image processing into growth commands to the sclera, have been studied and more will be introduced in the future. Microarray analyses of retinal and scleral transcripts following alterations in visual experience, or in knock-out models, have been presented and will
326 F. Schaeffel
help to identify new pharmacological targets for inhibition of myopia. Finally, screening of drugs against myopia may work well in mice since the drug can be given as eye drops (not as intravitreal injection as in chickens) and can reach retinal and scleral targets in sufficient concentrations due to the small volume of the globe.
Acknowledgments
Supported by the German Research Council DFG-Scha 518/13-1.
References
1.Schaeffel F, Burkhardt E. (2002) Measurement of refractive state and deprivation myopia in the black wild-type mouse. Invest Ophthalmol Vis Sci 43: ARVO e-abstract 182.
2.Tejedor J, de la Villa P. (2003) Refractive changes induced by form deprivation in the mouse eye. Invest Ophthalmol Vis Sci 44: 32–36.
3.Wallman J, Turkel J, Trachtman J. (1978) Extreme myopia produced by modest change in early visual experience. Science 201: 1249–1251.
4.Norton TT. (1990) Experimental myopia in tree shrews. Ciba Found Symp 155: 178–194.
5.Wiesel TN, Raviola E. (1977) Myopia and eye enlargement after neonatal lid fusion in monkeys. Nature 266: 66–68.
6.McFadden S, Wallman J. (1995) Guinea pig eye growth compensates for spectacle lenses. Invest Ophthalmol Vis Sci 36: S758 (ARVO abstract).
7.Remtulla S, Hallett PE. (1985) A schematic eye for the mouse, and comparisons with the rat. Vision Res 25: 21–31.
8.Schaeffel F. (2008) The mouse as a model for myopia, and optics of its eye. In: L Chalupa & RW Williams (eds), Eye, Retina and Visual System of the Mouse, pp 73–87. MIT Press.
9.Porciatti V, T Pizzorusso, L Maffei. (1999) The visual physiology of the wild type mouse determined with pattern VEPs. Vision Res 39: 3071–3081.
10.de la Cera EG, Rodriguez G, Llorente L, et al. (2006). Optical aberrations in the mouse eye. Vision Res 46: 2546–2553.
11.Carter-Dawson LD, LaVail MM. (1979) Rods and cones in the mouse retina. I. Structural analysis using light and electron microscopy. J Comp Neurol 15: 245–262.
12.Oyster CW. (1999) The Human Eye: Structure and Function, chapter 15. Sinauer Associates, Inc. Sunderland, Massachusetts.
327The Mouse Model of Myopia
13.Dangata YY, Findlater GS, Kaufman MH. (1995) Morphometric analysis of myelinated fiber composition in the optic nerve of adult C57BL and CBA strain mice and (C57BL x CBA) F1 hybrid: A comparison of interstrain variation. J Anat 186: 343–348.
14.Schmucker C, Seeliger M, Humphries P, et al. (2005) Grating acuity at different luminances in wild-type mice and in mice lacking rod or cone function.
Invest Ophthalmol Vis Sci 46: 398–407.
15.Schmucker C, Schaeffel F. (2004) A paraxial schematic eye model for the growing C57BL/6 mouse. Vision Res 44: 1857–1867.
16.Schaeffel F, Howland HC. (1988) Visual optics in normal and ametropic chickens. Clin Vis Sci 3: 83–98.
17.Zhou G, Williams RW. (1999) Eye1 and Eye2: gene loci that modulate eye size, lens weight, and retinal area in the mouse. Invest Ophthalmol Vis Sci 40: 817–825.
18.Zhou X, Shen M, Xie J, et al. (2008) The development of the refractive status and ocular growth in C57BL/6 mice. Invest Ophthalmol Vis Sci 49: 5208–5214
19.Zhou X, Xie J, Shen M, et al. (2008) Biometric measurement of the mouse eye using optical coherence tomography with focal plane advancement. Vis Res 48: 1137–1143.
20.Tkatchenko TV, Shen Y, Tkatchenko AV. (2010) Analysis of postnatal eye development in the mouse with high-resolution animal MRI. Invest Ophthamol Vis Sci 51: 21–27.
21.Barathi VA, Boopathi VG, Yap EPH, Beuerman RW. (2008) Two models of experimental myopia in the mouse. Vision Res 48: 904–916.
22.Schaeffel F, Burkhardt E, Howland HC, Williams RW. (2004) Measurement of refractive state and deprivation myopia in two strains of mice. Optom Vis Sci 81: 99–110.
23.Jiang L, Schaeffel F, Zhou X, et al. (2009) Spontaneous axial myopia and emmetropization in a strain of wild-type guinea pig (Cavia porcellus). Invest Ophthalmol Vis Sci 50: 1013–1019.
24.Howlett MH, McFadden SA. (2006) Form deprivation myopia in the guinea pig (Cavia procellus). Vision Res 46: 267–283.
25.Pardue MT, Faulkner AE, Fernandes A, et al. (2008) High susceptibility to experimental myopia in a mouse model with a retinal ON pathway defect.
Invest Ophthalmol Vis Sci 49: 706–712.
26.Glickstein M, Millodot M. (1970) Retinoscopy and eye size. Science 168: 605–606.
27.Schippert R, Burkhardt E, Feldkaemper M, Schaeffel F. (2007) Relative axial myopia in an EGR-1 (ZENK) knock-out mouse. Invest Ophthalmol Vis Sci 48:
11–17.
28.Schaeffel F, Howland HC, Farkas L. (1986) Natural accommodation in the growing chicken. Vision Res 26: 1977–1993.
328F. Schaeffel
29.Schaeffel F, Wagner H. (1996) Emmetropization and optical development in the eye of the barn owl (Tyto alba). J Comp Physiol A 178: 717–734.
30.Tkatchenko AV, Tkatchenko TV. (2009) Analysis of postnatal mouse eye growth and plasticity with high-resolution small animal MRI. Invest Ophthalmol Vis Sci 50: #3938 (ARVO abstract).
31.Faulkner AE, Kim MK, Iuvone PM, Pardue MT. (2007) Head-mounted goggles for murine form deprivation myopia. J Neurosci Methods 161: 96–100.
32.Li T, Howland HC, Troilo D. (2000) Diurnal illumination patterns affect the development of the chick eye. Vision Res 40: 2387–2393.
33.Beuerman RW, Barathi A, Weon SR, Tan D. (2003). Two models of experimental myopia in the mouse. Invest Ophthalmol Vis Sci ARVO e-abstract 4338.
34.Drager UC. (1975) Receptive fields of single cells and topography in mouse visual cortex. J Comp Neurol 160: 269–290.
35.Mathis U, Schaeffel F, Howland HC. (1988) Visual optics in toads (Bufo americanus). J Comp Physiol A 163: 201–213.
36.Schaeffel F, Hagel G, Eikermann J, Collett T. (1994) Lower-field myopia and astigmatism in amphibians and chickens. J Opt Soc Am A 11: 487–495.
37.Schaeffel F, Mathis U. (1991) Underwater vision in semi-aquatic European snakes. Naturwissenschaften 78: 373–375.
38.Pennesi ME, Lyubarsky AL, Jr Pugh EN. (1998) Extreme responsiveness of the pupil of the dark-adapted mouse to steady retinal illumination. Invest Ophthalmol Vis Sci 39: 2148–2156.
39.Woolf D. (1956) A comparative cytological study of the ciliary muscle.
Anatomical Record 124: 145–163.
40.Smith SS, Sundberg JP, John SWM. (2002) The anterior segment and ocular adnexae. In: RS Smith (ed), Systematic Evaluation of the Mouse Eye: Anatomy, Pathology and Biomethods, pp 3–24. CRC Press LLC, Boca Raton.
41.Lorente de No R. (1933) The interaction of the corneal reflex and vestibular nystagmus. Am J Physiol CIII: 704–711.
42.Pachter BR, Davidaowitz J, Breinin GM. (1976) Morphological fiber types of retractor bubli muscle in mouse and rat. Invest Ophthalmol 15: 654–657.
44.Howland HC, Sayles N. (1985) Photokeratometric and photorefractive measurements of astigmatism in infants and young children. Vision Res 25: 73–81.
45.Fernandes A, Yin H, Byron EA, et al. (2004) Effects of form deprivation on eye size and refraction in C57BL/6J mouse. Invest Ophthalmol Vis Sci 45: ARVO e-abstract 4280.
46.Schmucker C, Schaeffel F. (2004) In vivo biometry in the mouse eye with low coherence interferometry. Vision Res 44: 2445–2456.
47.Puk O, Dalke C, Favor J, et al. (2006) Variations of eye size parameters among different strains of mice. Mamm Genome 17: 851–857.
48.Artal P, Herreros de Tejada P, Munoz Tedo C, Green DG. (1998) Retinal image quality in the rodent eye. Vis Neurosci 15: 597–605.
329The Mouse Model of Myopia
49.Birch D, Jacobs GH. (1979) Spatial contrast sensitivity in albino and pigmented rats. Vision Res 19: 933–938.
50.Schmucker C, Schaeffel F. (2006) Contrast sensitivity of wild-type mice wearing diffusers or spectacle lenses, and the effect of atropine. Vision Res 46: 678–687.
51.Prusky GT, West PW, Douglas RM. (2000) Behavioral assessment of visual acuity in mice and rats. Vision Res 40: 2201–2209.
52.Wong AA, Brown RE. (2006) Visual detection, pattern discrimination and visual acuity in 14 strains of mice. Genes Brain Behav 5: 389–403.
53.Prusky GT, Alam NM, Beekman S, Douglas RM. (2004) Rapid quantification of adult and developing mouse spatial vision using a virtual optomotor system. Invest Ophthalmol Vis Sci 45: 4611–4616.
54.Prusky GT, Alam NM, Douglas RM. (2006) Enhancement of vision by monocular deprivation in adult mice. J Neurosci 26: 11554–11561.
55.Douglas RM, Alam NM, Silver BD, et al. (2005) Independent visual threshold measurements in the two eyes of freely moving rats and mice using a virtualreality optokinetic system. Vis Neurosci 22: 677–684.
56.Umino Y, Solessio E, Barlow RB. (2008) Speed, spatial and temporal tuning of rod and cone vision in mouse. J Neurosci 28: 189–198.
57.Puk O, Dalke C, Hrabé de Angelis M, Graw J. (2008) Variation of the response to the optokinetic drum among various strains of mice. Front Biosci 13: 6269–6275.
58.Prusky GT, Douglas RM. (2004) Characterization of mouse cortical spatial vision. Vision Res 44: 3411–3418.
59.Valmaggia C, A Rütsche, A Baumann, et al. (2004) Age related change of optokinetic nystagmus in healthy subjects: a study from infancy to senescence. Br J Ophthalmol 88: 1577–1581.
60.Thaung C, Arnold K, Jackson IJ, Coffey PJ. (2002) Presence of visual head tracking differentiates normal sighted from retinal degenerate mice. Neurosci Lett 325: 21–24.
61.Alphen van B, Winkelman BHJ, Frens MA. (2009) Ageand sex-related differences in contrast sensitivity in C57BL/6 mice. Invest Ophthalmol Vis Sci 50: 2451–2458.
62.Faulstich M, van Alphen AM, Luo C, et al. (2006) Oculomotor plasticity
during vestibular compensation does not depend on cerebellar LTD.
J Neurophysiol 96: 1187–1195.
63.Abdeljalil J, Hamid M, Abdel-Mouttalib O, et al. (2005) The optomotor response: a robust first-line visual screening method for mice. Vision Res 45: 1439–1446.
64.Sterling P. (2003) How retinal circuits optimize the transfer of visual information. In: LM Chalupa & JS Werner (eds), The Visual Neurosciences, Vol 1, pp 234–259. MIT press, Cambridge, Massachusetts.
330F. Schaeffel
65.Faulkner AE, Pozdeyev N, Iuvone PM, Pardue MT. (2009) The effect of lens defocus versus form deprivation on refractive status and dopamine in Nob mice. Invest Ophthalmol Vis Sci 50: #3846 (ARVO abstract).
66.Fischer AJ, McGuire JJ, Schaeffel F, Stell WK. (1999) Lightand focus-depend- ent expression of the transcription factor ZENK in the chick retina. Nat Neurosci 2: 706–712.
67.Bitzer M, Schaeffel F. (2002) Defocus-induced changes in ZENK expression in the chicken retina. Invest Ophthalmol Vis Sci 43: 246–252.
68.Schippert R, Schaeffel F, Feldkaemper M. (2009) Microarray analysis of retinal gene expression in Egr-1 knock-out mice. Mol Vis 15: 2720–2739.
69.Zhou X, Huang Q, An J, et al. (2009) The relative myopia in mice deficient in adenosine A2a receptors is associated with reduced collagen synthesis in sclera. Invest Ophthalmol Vis Sci 50: #3839 (ARVO abstract).
70.Faulkner AE, Choi HY, Kim MK, et al. (2007) Retinal defects influenece unmanipulated refractive development in mice. Invest Ophthalmol Vis Sci 48: #4419 (ARVO abstract).
71.Barathi VA, Beuerman RW, Schaeffel F. (2009) Effect of unilateral topical atropine on binocular pupil responses and eye growth in mice. Vision Res 49: 383–387.
72.Diether S, Schaeffel F, Lambrou GN, et al. (2007) Effects of intravitreally and intraperitoneally injected atropine on two types of experimental myopia in chicken. Exp Eye Res 84: 266–274.
73.Barathi VA, Weon SR, Beuerman RW. (2009) Expression of muscarinic receptors in human and mouse sclera and their role in the regulation of scleral fibroblast proliferation. Mol Vis 15: 1277–1293.
74.Brand C, Burkhardt E, Schaeffel F, et al. (2005) Regulation of Egr-1, VIP, and Shh mRNA and Egr-1 protein in the mouse retina by light and image quality. Mol Vis 11: 309–320.
75.Brand C, Schaeffel F, Feldkaemper M. (2007) A microarray analysis of retinal transcripts that are controlled by retinal image contrast in mice. Mol Vis 13: 920–932.
76.Beuerman RW, Barathi VA, Rhuan WS, Chew J. (2009) Role of transglutaminase 2 (TGM-2) in mouse after induction of experimental myopia. In: McBrien, et al. Myopia: Recent advances. Opt Vis Sci 86: 45–66.
77.Beuerman RW, Barathi A, Zhou L. (2009) Quantitative analysis of the retina proteome in a mouse model of myopia. Invest Ophthalmol Vis Sci 50: #3830 (ARVO abstract).
78.Green DG, Powers MK, Banks MS. (1980) Depth of focus, eye size and visual acuity. Vision Res 20: 827–823.