Partial retinal photoreceptor loss in a transgenic mouse model associated with reduced levels of interphotoreceptor retinol binding protein (IRBP, RBP3)

Yi-Hsia Liu, Clare Corbett, Izabela P Klaska, Kimmo Makinen, John M Nickerson, Richard J Cornall, Lucia Kuffova, John V Forrester

Research output: Contribution to journalArticle

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Abstract

Organ-specific transgenic membrane expression of hen egg lysozyme (HEL) as a "neo-self antigen" has been used in several models to study immunological tolerance. In this study we report the changes which occur in the B10.BR mouse retina when membrane-bound HEL is expressed in photoreceptors under the control of the promoter for interphotoreceptor retinoid binding protein (IRBP, RBP3). On direct clinical examination of the single transgenic (sTg-IRBP:HEL) mouse fundus, a low-level increase in retinal degeneration compared to non-transgenic controls was observed, presenting as drusenoid deposits and occasional small patches of atrophy. On histological examination, there was an overall shortening of outer segments and loss of photoreceptor nuclei in sTg-IRBP:HEL mice, which was more pronounced in the retinal periphery, particularly inferiorly. The fundoscopically observed lesions did not correlate with the photoreceptor shortening/loss but appeared to be located at the level of the retinal pigment epithelium/choriocapillaris layer and were an exaggeration in size and number of similar age-related changes found in wild type (WT) mice. In addition, neither the atrophic lesions nor the photoreceptor shortening were associated with common retinal degeneration genes, nor were they caused by exposure to light damage since mice housed at both high and low ambient light levels had similar degrees of retinal degeneration. Instead, sTg-IRBP:HEL mice expressed reduced levels of soluble retinal IRBP compared to WT mice which were present from postnatal day16 (P16) and preceded development of photoreceptor shortening (onset P21). We propose that insertion of the HEL transgene in the photoreceptor membrane disrupted normal photoreceptor function and led to reduced levels of soluble IRBP and retinal thinning. A similar phenotype has been observed in IRBP deficient mice. Despite the retinal thinning, the amount of HEL expressed in the retina was sufficient to act as an autoantigenic target when the mice were crossed to the HEL T cell receptor Tg mouse, since double transgenic (dTg-IRBP:HEL) mice spontaneously developed a severe uveoretinitis with onset at weaning. We suggest that, although membrane expression of foreign transgene products is likely to modify the structure and function of tissues and cells, the technology provides useful models to investigate mechanisms of antigen-specific immunological tolerance.

Original languageEnglish
Pages (from-to)54-65
Number of pages12
JournalExperimental Eye Research
Volume172
Early online date21 Mar 2018
DOIs
Publication statusPublished - 31 Jul 2018

Fingerprint

Vertebrate Photoreceptor Cells
Transgenic Mice
Retinal Degeneration
Membranes
Transgenes
Retina
interstitial retinol-binding protein
hen egg lysozyme
Light
Retinal Pigment Epithelium
Autoantigens
T-Cell Antigen Receptor
Weaning
Atrophy

Keywords

  • Journal Article
  • Transgenic
  • Hen egg lysozyme (HEL)
  • Photoreceptor
  • Retinal degeneration
  • EAU

Cite this

Partial retinal photoreceptor loss in a transgenic mouse model associated with reduced levels of interphotoreceptor retinol binding protein (IRBP, RBP3). / Liu, Yi-Hsia; Corbett, Clare; Klaska, Izabela P; Makinen, Kimmo; Nickerson, John M; Cornall, Richard J; Kuffova, Lucia; Forrester, John V.

In: Experimental Eye Research, Vol. 172, 31.07.2018, p. 54-65.

Research output: Contribution to journalArticle

Liu, Yi-Hsia ; Corbett, Clare ; Klaska, Izabela P ; Makinen, Kimmo ; Nickerson, John M ; Cornall, Richard J ; Kuffova, Lucia ; Forrester, John V. / Partial retinal photoreceptor loss in a transgenic mouse model associated with reduced levels of interphotoreceptor retinol binding protein (IRBP, RBP3). In: Experimental Eye Research. 2018 ; Vol. 172. pp. 54-65.
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note = "Acknowledgements: We thank Gillian Milne and Microscopy and Histology Core Facility at the University of Aberdeen for the help with histology. This work was generously funded by the charity Saving Sight in Grampian and the University of Aberdeen Development Trust. JN is funded by R01EY021592, R01EY016470, P30EY006360, and an unrestricted grant to the Department of Ophthalmology at Emory University from Research to Prevent Blindness, Inc. Mutant DNAs from Pde6b, Prph2 and Crb1 mice were kindly provided by Dr. Chang Bo and Mr. FitzMaurice Bernard (Jackson Laboratory).",
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T1 - Partial retinal photoreceptor loss in a transgenic mouse model associated with reduced levels of interphotoreceptor retinol binding protein (IRBP, RBP3)

AU - Liu, Yi-Hsia

AU - Corbett, Clare

AU - Klaska, Izabela P

AU - Makinen, Kimmo

AU - Nickerson, John M

AU - Cornall, Richard J

AU - Kuffova, Lucia

AU - Forrester, John V

N1 - Acknowledgements: We thank Gillian Milne and Microscopy and Histology Core Facility at the University of Aberdeen for the help with histology. This work was generously funded by the charity Saving Sight in Grampian and the University of Aberdeen Development Trust. JN is funded by R01EY021592, R01EY016470, P30EY006360, and an unrestricted grant to the Department of Ophthalmology at Emory University from Research to Prevent Blindness, Inc. Mutant DNAs from Pde6b, Prph2 and Crb1 mice were kindly provided by Dr. Chang Bo and Mr. FitzMaurice Bernard (Jackson Laboratory).

PY - 2018/7/31

Y1 - 2018/7/31

N2 - Organ-specific transgenic membrane expression of hen egg lysozyme (HEL) as a "neo-self antigen" has been used in several models to study immunological tolerance. In this study we report the changes which occur in the B10.BR mouse retina when membrane-bound HEL is expressed in photoreceptors under the control of the promoter for interphotoreceptor retinoid binding protein (IRBP, RBP3). On direct clinical examination of the single transgenic (sTg-IRBP:HEL) mouse fundus, a low-level increase in retinal degeneration compared to non-transgenic controls was observed, presenting as drusenoid deposits and occasional small patches of atrophy. On histological examination, there was an overall shortening of outer segments and loss of photoreceptor nuclei in sTg-IRBP:HEL mice, which was more pronounced in the retinal periphery, particularly inferiorly. The fundoscopically observed lesions did not correlate with the photoreceptor shortening/loss but appeared to be located at the level of the retinal pigment epithelium/choriocapillaris layer and were an exaggeration in size and number of similar age-related changes found in wild type (WT) mice. In addition, neither the atrophic lesions nor the photoreceptor shortening were associated with common retinal degeneration genes, nor were they caused by exposure to light damage since mice housed at both high and low ambient light levels had similar degrees of retinal degeneration. Instead, sTg-IRBP:HEL mice expressed reduced levels of soluble retinal IRBP compared to WT mice which were present from postnatal day16 (P16) and preceded development of photoreceptor shortening (onset P21). We propose that insertion of the HEL transgene in the photoreceptor membrane disrupted normal photoreceptor function and led to reduced levels of soluble IRBP and retinal thinning. A similar phenotype has been observed in IRBP deficient mice. Despite the retinal thinning, the amount of HEL expressed in the retina was sufficient to act as an autoantigenic target when the mice were crossed to the HEL T cell receptor Tg mouse, since double transgenic (dTg-IRBP:HEL) mice spontaneously developed a severe uveoretinitis with onset at weaning. We suggest that, although membrane expression of foreign transgene products is likely to modify the structure and function of tissues and cells, the technology provides useful models to investigate mechanisms of antigen-specific immunological tolerance.

AB - Organ-specific transgenic membrane expression of hen egg lysozyme (HEL) as a "neo-self antigen" has been used in several models to study immunological tolerance. In this study we report the changes which occur in the B10.BR mouse retina when membrane-bound HEL is expressed in photoreceptors under the control of the promoter for interphotoreceptor retinoid binding protein (IRBP, RBP3). On direct clinical examination of the single transgenic (sTg-IRBP:HEL) mouse fundus, a low-level increase in retinal degeneration compared to non-transgenic controls was observed, presenting as drusenoid deposits and occasional small patches of atrophy. On histological examination, there was an overall shortening of outer segments and loss of photoreceptor nuclei in sTg-IRBP:HEL mice, which was more pronounced in the retinal periphery, particularly inferiorly. The fundoscopically observed lesions did not correlate with the photoreceptor shortening/loss but appeared to be located at the level of the retinal pigment epithelium/choriocapillaris layer and were an exaggeration in size and number of similar age-related changes found in wild type (WT) mice. In addition, neither the atrophic lesions nor the photoreceptor shortening were associated with common retinal degeneration genes, nor were they caused by exposure to light damage since mice housed at both high and low ambient light levels had similar degrees of retinal degeneration. Instead, sTg-IRBP:HEL mice expressed reduced levels of soluble retinal IRBP compared to WT mice which were present from postnatal day16 (P16) and preceded development of photoreceptor shortening (onset P21). We propose that insertion of the HEL transgene in the photoreceptor membrane disrupted normal photoreceptor function and led to reduced levels of soluble IRBP and retinal thinning. A similar phenotype has been observed in IRBP deficient mice. Despite the retinal thinning, the amount of HEL expressed in the retina was sufficient to act as an autoantigenic target when the mice were crossed to the HEL T cell receptor Tg mouse, since double transgenic (dTg-IRBP:HEL) mice spontaneously developed a severe uveoretinitis with onset at weaning. We suggest that, although membrane expression of foreign transgene products is likely to modify the structure and function of tissues and cells, the technology provides useful models to investigate mechanisms of antigen-specific immunological tolerance.

KW - Journal Article

KW - Transgenic

KW - Hen egg lysozyme (HEL)

KW - Photoreceptor

KW - Retinal degeneration

KW - EAU

U2 - 10.1016/j.exer.2018.03.020

DO - 10.1016/j.exer.2018.03.020

M3 - Article

VL - 172

SP - 54

EP - 65

JO - Experimental Eye Research

JF - Experimental Eye Research

SN - 0014-4835

ER -