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(Investigative Ophthalmology and Visual Science. 2000;41:3128-3133.)
© 2000 by The Association for Research in Vision and Ophthalmology, Inc.

Retinal Dysfunction in Basigin Deficiency

Kenji Hori1, Naomi Katayama4, Shu Kachi1,2, Mineo Kondo1, Kenji Kadomatsu3, Jiro Usukura2, Takashi Muramatsu3, Shigeo Mori4 and Yozo Miyake1

From the 1 Departments of Ophthalmology, 2 Anatomy, and 3 Biochemistry, Nagoya University School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, Japan; and 4 Space Medicine Research Center, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
PURPOSE. To examine the retina of basigin (Bsg) knockout mice by electrophysiological and histologic methods and thereby to determine the possible function of Bsg in phototransduction and retinal development.

METHODS. Scotopic and photopic electroretinograms (ERGs) were recorded from 11 wild-type, 12 heterozygous, and 8 homozygous Bsg gene knockout mice of different ages. The retinas were also examined by histologic and immunolabeling methods.

RESULTS. Bsg knockout mice of 5 to 41 weeks of age showed a decrease in the amplitude of all components of both the photopic and scotopic ERGs. In contrast, the fundus and the fluorescein fundus angiography and morphology of the retina at the light microscopic level appeared to be normal until 8 weeks of age in Bsg knockout mice. Thereafter, the length of outer segment and outer nuclear layers decreased with increasing age. Immunohistochemical analysis localized Bsg protein in a variety of cells in the retina, especially in the pigment epithelium, the upper outer plexiform layer and the inner segments of photoreceptor cells.

CONCLUSIONS. The results demonstrated that both rod and cone function were severely affected from an early age by the targeted disruption of the Bsg gene. In spite of abnormal ERGs, the photoreceptor cells maintained normal morphology up to 8 weeks. Thereafter, the photoreceptor cells degenerated gradually and were almost ablated by 41 weeks.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Basigin (Bsg) is a transmembrane glycoprotein belonging to the immunoglobulin (Ig) superfamily and has two Ig domains. Its protein portion is 27 kDa, and its glycosylated form is 43 to 66 kDa.1 2 Homologous Bsgs have been found in different species of animals. Chicken Bsg (HT7/neurothelin/5A11) has been implicated in the construction of the blood–brain barrier (BBB) because of its specific localization in capillary endothelial cells in the brain,3 4 and in neuronal–glial interactions in the retina during development.5 Human Bsg (M6/EMMPRIN) is induced during leukocyte activation6 and can induce matrix metalloproteases in fibroblasts.7 Strong expression of mouse Bsg (gp42) and rat Bsg (OX-47/CE9) has been detected in the brain as well as other organs, including testis, kidney, heart, liver, and small intestine,1 2 8 9 10 suggesting that Bsg has diverse biological functions in mammals.

To determine the function of Bsg in the retina, we generated Bsg knockout (Bsg-/-) mice.11 12 Many Bsg-/- mice were lost because of impaired implantation. Half of the surviving Bsg-/- mice had interstitial pneumonia and died within 4 weeks after birth. Both male and female Bsg-/- mice are infertile, and new progenies were obtained by crossing heterozygous pairs.12

Bsg-/- mice also showed poor performance in learning and memory.13 In addition, they showed decreased sensitivity to irritating odors11 and increased sensitivity to electric foot-shock.13 Unexpectedly, the BBB was not affected in the Bsg-/- mice.11 In addition to these neurologic phenotypes, we have noticed a characteristic visual behavior: Bsg-/- mice take longer to enter a dark compartment. This suggested that Bsg-/- mice may be less sensitive to light than wild-type (Bsg+/+) and heterozygous (Bsg+/-) mice.13 This desensitization to light could be caused by the absence of Bsg in the retina, where Bsg mRNA is strongly expressed.14

To determine the function of Bsg in the retina, we examined the retina of Bsg-/- mice using electroretinography (ERG) and morphologic and immunohistochemical methods.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
The Bsg-/- mice used in this study were from the same line as those used in a previous study.12 They have a hybrid background of 129/SV x C57/BL6, and mice at the F5~F7 generation were used. Each Bsg-/- mouse was a littermate of a Bsg+/+, a Bsg+/-, or both. The number and ages of the mice at the time of the ERG recordings are shown in Table 1 . Histologic analysis was performed on all mice within 14 days of the ERG recordings.


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  		Table 1. Number and Age Distribution of Mice for ERG Recording

 
ERG Examination
Scotopic and photopic ERGs were recorded from the three types of mice at different ages. For scotopic ERG recordings, the animals were dark-adapted overnight and anesthetized with an intraperitoneal injection of a saline solution (15 µl/g) containing ketamine (1 mg/ml), xylazine (0.4 mg/ml), and urethane (40 mg/ml).15 The animals were prepared for the ERG recordings under deep red-light illumination. The pupil was dilated with 0.5% tropicamide and 0.5% phenylephrine hydrochloride. The mice were held loosely in a mouse-restraining pocket and placed on a heating pad.

ERGs were recorded from the corneal surface with a coiled platinum wire that made contact through a thin layer of 1% methylcellulose. A similar wire placed in the conjunctival sac, and a needle electrode was inserted in the tail served as the reference and ground electrodes, respectively. ERGs were amplified by 1000x with a bandpass of 1 to 300 Hz. The ERGs were stored in a computer (V 3.5; Mac Laboratory, Sladstone, Australia) for later analysis.

Strobe flash stimuli were presented in a Ganzfeld bowl (Full Field Ganzfeld Stimulator Model GS 2000; LACE Elettronica sel via Marmicciolo, Pisa, Italy), and the radius of the bowl was 20 cm. The mouse was placed in the bowl to receive uniform illumination on the cornea. This position was approximately 15 cm from the closest surface. The luminance of the stimulus was measured by placing the detector of a light meter (DR-2550; Gammma Scientific Co., San Diego, CA) at the position of the mouse’s cornea. The maximum luminance was 1.0 log cd-sec/m2 (photopic unit), and neutral density filters were used to reduce the full-intensity stimulus. Nine steps of stimulus intensities ranging from -6.2 to 1.0 log cd-sec/m2 were used for the scotopic ERG recordings, with an interstimulus interval of 1 minute. The photopic ERGs were recorded under a steady, white background illumination of 40 cd/m2, and the stimulus intensity ranged from -0.8 to 1.0 log cd-sec/m2. Sixty-four responses were averaged for photopic ERGs.

Fundus Examination
Fundus photographs and fluorescein fundus angiograms were taken after the ERG recordings. Sodium fluorescein of 0.05 ml was injected into the tail vein, and the fundus was photographed with a fundus camera (Kowa, Nagoya, Japan).

Histologic Analysis
The retinas were fixed in 2.5% glutaraldehyde and 2% paraformaldehyde in 0.1 M sodium cacodylate buffer, pH 7.4, at 4°C for 1.5 hour and postfixed in 1% osmium oxide in the same buffer at 4°C for 1 hour. The specimens were dehydrated with ascending series of ethanol and embedded in Polybed 812 epoxy resin (Polyscience, Warminster, PA). Semi-thin sections stained with toluidine blue were used for light microscopic observation.

Immunohistochemical Analysis
The retinas were fixed with 4% paraformaldehyde in phosphate buffer adjusted to pH 7.4 and equilibrated with 30% sucrose. According to the manufacturer’s protocol, frozen sections of 15 µm thickness were cut with a cryostat (Leica Co. Ltd., Wetzlar, Germany) and mounted on silanized glass slides. The sections were incubated first with anti-Bsg antibody15 diluted 1:100 with phosphate-buffered saline (PBS) containing 1% bovine serum albumin and 0.1% Triton X-100. After washing in PBS, the sections were further incubated with FITC-labeled goat anti-rabbit IgG diluted 1:50 with PBS at room temperature for 30 minutes. The sections were examined under a fluorescence microscope after several washes with PBS. For control, sections were incubated with nonimmune rabbit serum instead of anti-Bsg antibody.

These mice were produced and maintained in the Institute for Laboratory Animal Research at Nagoya University School of Medicine and were handled in accordance with the guidelines established by the institute. These experiments adhere to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
ERG Findings
Examples of the scotopic ERGs recorded from the three types of mice at the age of 33 weeks are shown in Figure 1 . The ERGs of the Bsg+/- mouse were similar to those of Bsg+/+ and were comparable to the ERGs recorded from other types of normal mice. The ERGs of the Bsg-/- mouse were very different; the stimulus intensity threshold was higher, and the amplitudes were lower. In addition, the peak latency of the b-wave at all recordable intensities was slightly longer in the Bsg-/- mice.



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  		Figure 1. Scotopic ERG responses of Bsg+/+, Bsg+/-, and Bsg-/- Basigin mice at 33 weeks of age. Maximum stimulus intensity is 1.0 log cd-sec/m2 and the stimulus intensity was attenuated with the neutral density filters.

 
From ERGs such as these, the amplitude and peak latency of the b-waves were measured for the ERGs evoked by the different stimulus intensities. In addition, the stimulus intensity threshold was determined. The intensity-response function of the scotopic b-wave amplitudes (Figs. 2A 2B) and peak latencies (Figs. 2C 2D) were plotted. The means ± SDs are shown. The results from the relatively young group (5–13 weeks; Figs. 2A 2C ) and relatively old group (33–44 weeks; Figs. 2B 2D ) are shown separately. At both ages, only the Bsg-/- mice showed a significant reduction in the amplitude and an elevated stimulus threshold (P < 0.001; two-way ANOVA) (Figs. 2A 2B) .



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  		Figure 2. Stimulus–response functions for the scotopic ERGs of Bsg+/+, Bsg+/-, and Bsg-/- mice. Left: stimulus intensity versus b-wave amplitude at age of 5 to 13 (A) and 33 to 43 weeks old (B). Right: stimulus intensity versus b-wave peak latency at age of 5 to 13 (C) and 33 to 43 weeks (D). In (A) and (C), the mean ± SD from 5 Bsg+/+, 8 Bsg+/-, and 4 Bsg-/- mice, and in (B) and (D), those from 4 Bsg+/+, 2 Bsg+/-, and 4 Bsg-/- mice are shown.

 
The peak latencies of the Bsg-/- mice were slightly longer than those of the Bsg+/+ and Bsg+/- mice for both age groups, but these changes were not statistically significant. The photopic ERGs obtained from the three types of mice at the age of 33 weeks are shown in Figure 3 , and the intensity-response functions are shown in Figure 4 . Similar to the scotopic ERG, only the Bsg-/- mice showed significantly reduced b-wave amplitudes and elevated stimulus thresholds (P < 0.001; two-way ANOVA). In addition, the b-wave peak latency did not show any significant difference among these three types of mice. The amplitudes of b-wave in the younger group did not show significant difference from those of the older group in both scotopic and photopic ERG.



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  		Figure 3. Photopic ERG responses of Bsg+/+, Bsg+/-, and Bsg-/- mice at 33 weeks of age.

 


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  		Figure 4. Stimulus–response functions for photopic ERG of Bsg+/+, Bsg+/-, and Bsg-/- mice. Left: stimulus intensity versus b-wave amplitude for ages 5 to 13 (A) and 33 to 43 weeks (B). Right: b-wave peak latency for ages 5 to 13 (C) and 33 to 43 weeks (D). In (A) and (C) , the mean ± SD from 5 Bsg+/+, 8 Bsg+/-, and 4 Bsg-/- mice, and in (B) and (D), those from 4 Bsg+/+, 2 Bsg+/-, and 4 Bsg-/- mice are shown.

 
Fundus
Fundus photographs (top) and fluorescein fundus angiography (bottom) of the three types of mice at 40 weeks of age are shown in Figure 5 . The appearance of the fundus of the Bsg-/- mice did not differ significantly from that of the Bsg+/+ or the Bsg+/- mice. Any kinds of significant anomaly were not observed in the appearance of the fundus of the Bsg-/- mice. However, some dark radial lines were observed around the fundus. Vessels in fundus of Bsg-/- mice also seemed to be slightly narrower than those in Bsg+/+ or Bsg+/- mice. In fluorescein fundus angiography, there was no abnormal leakage of fluorescence dye from the retinal capillaries and no hyperfluorescence of the retinal pigment epithelium.



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  		Figure 5. Fundus photographs (top) and fluorescein fundus angiograms 1 minute after the dye injection (bottom) in Bsg+/+ (A) , Bsg+/- (B), and Bsg-/- (C) mice of 30 to 50 weeks of age.

 
Histology
The retinas of Bsg-/- mice at 8 weeks of age appeared normal anatomically as a whole (Fig. 6A ). However, arrangement of outer segments was disordered partially from specimen to specimen at this age. Thereafter, the neural retina degenerated progressively with age with the characteristic changes observed in photoreceptor cell layer. At 35 weeks of age, the length of the outer segment was reduced to less than half of the normal length, and the thickness of the outer nuclear layer was reduced to four layers. These observations clearly indicate a degeneration of the photoreceptor cells. At 43 weeks of age, most photoreceptor cells were absent from the retina (Figs. 6B 6C) , but a few photoreceptor cells still remained.



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  		Figure 6. Morphologic changes in retinal photoreceptor layers of Bsg-/- mice at different ages. PE, Pigment epithelium; OS, outer segment; IS, inner segment; ONL, outer nuclear layer; INL, inner nuclear layer. (A) 8 weeks Bsg-/- retina. (B) 35 weeks Bsg-/- retina. (C) 43 weeks Bsg-/- retina. (D) 43 weeks Bsg+/+ retina. (E) 48 weeks Bsg+/- retina.

 
Immunohistochemistry
The anti-Bsg antibody binding sites were found predominantly in pigment epithelial cells and upper outer plexiform layer and inner segments of photoreceptor cells in Bsg+/+ and Bsg+/- mice (Fig. 7) . Immunoreactivity against anti-Bsg antibody was not detected in other parts of the retina at the light microscope level. In Bsg-/- mice and in wild-type mice (Bsg+/+) incubated with nonimmune rabbit serum, labeling with anti-Bsg antibody was not observed (for experimental control).



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  		Figure 7. Bsg immunohistochemistry in mouse retina of the three types and one control at age of 13 weeks. Control section was incubated with nonimmune rabbit serum instead of anti-Bsg antibody. PE, pigment epithelium; IS, inner segment; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer. (A) 13 weeks Bsg+/+ retina. (B) 13 weeks Bsg+/- retina. (C) 13 weeks Bsg-/- retina. (D) 13 weeks Bsg+/+ retina, experimental control.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our observations clearly demonstrated that the Bsg gene, a member of the immunoglobulin superfamily, plays a significant role in maintaining the photoexcitation process. The absence of the Bsg gene resulted in higher stimulus intensity thresholds and depressed b-waves beginning at an early age. There were, however, some unexpected findings in the Bsg knockout mice. The fundus and fluorescein angiography showed minimum changes, and the histologic abnormalities did not appear until 8 weeks of age. As described, the amplitudes of both the photopic and scotopic components of the ERGs were reduced significantly even at an early age, when the retinas appeared morphologically normal at the light microscope level. This suggests that the ERG abnormalities were independent of the structural degeneration of retina and may involve an alteration of a biochemical process.

Fluorescein fundus angiography (Fig. 5) demonstrated the absence of leakage in the Bsg-/- mice, suggesting that the blood–retinal barrier (BRB) was not severely damaged. This observation is in accord with the finding that the BBB was also not altered in Bsg-/- mice11 because they are both characterized by complexly arranged tight junctions between the barrier-forming cells and a paucity of endocytic vesicles within these cells.16 Involvement of Bsg in construction of the BBB was originally suggested because of the specific localization of chicken Bsg in the capillary endothelial cells in the brain.3 4 Our observation suggest that this does not appear to be the case in the mouse retina.

In immunohistochemical studies, Linser and Perkins17 and Fadool et al.18 reported that the anti-Bsg monoclonal antibody (5A11/HT7 in the chicken) recognized a 45.5- and a 69-kDa membrane protein present on mature retinal cells, especially Möller and photoreceptor cells. Tests on the maturation of retinal Möller cells in vitro implicated this antigen in heterotypic cell–cell interactions in the developing retina. In our data (Fig. 7) , however, anti-Bsg antibody binding sites were found predominantly on the retinal pigment epithelium cells and synaptic terminal of photoreceptor cells in both Bsg+/+ and Bsg+/- mice. Such differences in labeling pattern between our data and others might be due, in part, to species differences. In addition, the antibody used in this study is a rabbit polyclonal antibody against the ectodomain of mouse Bsg, although others used two monoclonal IgG antibodies (5A11 mab and 3B7). Different antibodies could recognize different epitopes. This might be another reason for the differences. Our results are in agreement with the report by Neil and Barnstable19 that rat Bsg (RET-PE2) is predominantly expressed on the pigment epithelium. Thus, it is difficult to estimate the role of Bsg in the photoexcitation process from the present immunohistochemical data.

Histologic study (Fig. 6) showed that the 8-week-old Bsg-/- mouse retina maintained relatively normal morphology at the light microscopic level in spite of the severely reduced ERG. As described in results, however, the arrangement of outer segments appeared variably disordered among the knockout mice of a given stage of maturation. In the 35-week-old Bsg-/- mouse retina, four layers of photoreceptor cells were observed, and the 43-week-old Bsg-/- mouse contained only one or two layers of photoreceptor cells, indicating progressive degeneration of photoreceptor cells. Such a discrepancy between morphologic and functional abnormality is striking and interesting. It is obvious that Bsg is involved in some steps of photoexcitation process but not in morphogenesis. The late morphologic degeneration of the photoreceptor might be triggered by some stress induced from the long-term malfunction of the photoreceptors. If the mechanism for the photoreceptor dysfunction can be corrected before the morphologic degeneration takes place, normal retinal function activity may be rescued. Bsg knockout mice are expected to be valuable as a model animal to treat retinal degeneration by various methods including gene transfer.


   Acknowledgements
 
The authors thank Satoshi Yamamoto for taking care of the mice.


   Footnotes
 
Supported by Grants 10178102 and 11670114 from Ministry of Education, Science, Sports, and Culture, Japan.

Submitted for publication December 10, 1999; revised March 31, 2000; accepted April 24, 2000.

Commercial relationships policy: N.

Corresponding author: Yozo Miyake, Department of Ophthalmology, Nagoya University School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan. ymiyake{at}med.nagoya-u.ac.jp


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Miyauchi, T, Kanekura, T, Yamaoka, A, Ozawa, M, Miyazawa, S, Muramatsu, T. (1990) Basigin, a new, broadly distributed member of the immunoglobulin superfamily, has strong homology with both the immunoglobulin V domain and the ß-chain of major histocompatibility complex class II antigen J Biochem 107,316-323[Abstract/Free Full Text]
  2. Altruda, F, Cervella, P, Gaeta, ML, et al (1989) Cloning of cDNA for a novel mouse membrane glycoprotein (gp42): shared identity to histocompatibility antigens, immunoglobulins and neural-cell adhesion molecules Gene 85,445-452[Medline][Order article via Infotrieve]
  3. Risau, W, Hallmann, R, Albrecht, U, Henke-Fahle, S. (1986) Brain induces the expression of an early cell surface marker for blood-brain barrier-specific endothelium EMBO J 5,3179-3183[Medline][Order article via Infotrieve]
  4. Schlosshauer, B, Herzog, K-H. (1990) Neurothelin. An inducible cell surface glycoprotein of blood-brain barrier-specific endothelial cells and distinct neurons J Cell Biol 110,1261-1274[Abstract/Free Full Text]
  5. Fadool, JM, Linser, PJ (1993) Differential glycosylation of the 5A11/HT7 antigen by neural retina and epithelial tissues in the chicken J Neurochem 60,1354-1364[Medline][Order article via Infotrieve]
  6. Kasinrerk, W, Fiebiger, E, Stefanova, I, Baumruker, T, Knapp, W, Stockinger, H. (1992) Human leukocyte activation antigen M6, a member of the Ig superfamily, is the species homologue of rat OX-47, mouse basigin, and chicken HT7 molecule J Immunol 149,847-854[Abstract]
  7. Biswas, C, Zhang, Y, DeCastro, R, et al (1995) The human tumor cell-derived collagenase stimulatory factor (renamed EMMPRIN) is a member of the immunoglobulin superfamily Cancer Res 55,434-439[Abstract/Free Full Text]
  8. Fossum, S, Mallett, S, Barclay, AN (1991) The MRC OX-47 antigen is a member of the immunoglobulin superfamily with an unusual transmembrane sequence Eur J Immunol 21,671-679[Medline][Order article via Infotrieve]
  9. Nehme, CL, Cesario, MM, Myles, DG, Koppel, DE, Bartles, JR (1993) Breaching the diffusion barrier that compartmentalizes the transmembrane glycoprotein CE9 to the posterior-tail plasma membrane domain of the rat spermatozoon J Cell Biol 120,687-694[Abstract/Free Full Text]
  10. Nehme, CL, Fayos, BE, Bartles, JR (1995) Distribution of the integral plasma membrane glycoprotein CE9 (MRC OX-47) among rat tissues and induction by diverse stimuli of metabolic activation Biochem J 310,693-698
  11. Igakura, T, Kadomatsu, K, Taguchi, O, et al (1996) Roles of basigin, a member of the immunoglobulin superfamily, in behavior as to an irritating odor, lymphocyte response and blood brain barrier Biochem Biophys Res Commun 224,33-36[Medline][Order article via Infotrieve]
  12. Igakura, T, Kadomatsu, K, Kaname, T, et al (1998) A null mutation in basigin, an immunoglobulin superfamily member, indicates its important roles in peri-implantation development and spermatogenesis Dev Biol 194,152-165[Medline][Order article via Infotrieve]
  13. Naruhashi, K, Kadomatsu, K, Igakura, T, et al (1997) Abnormalities of sensory and memory functions in mice lacking Bsg gene Biochem Biophys Res Commun 236,733-737[Medline][Order article via Infotrieve]
  14. Fan, Q-W, Yuasa, S, Kuno, N, et al (1998) Expression of basigin, a member of the immunoglobulin superfamily, in the mouse central nervous system Neurosci Res 30,53-63[Medline][Order article via Infotrieve]
  15. Goto, Y, Peachey, NS (1996) Rod phototransduction in transgenic mice expressing a mutant opsin gene J Opt Soc Am A 13,577-585[Medline][Order article via Infotrieve]
  16. Janzer, RC (1993) The blood-brain barrier: Cellular basis J Inher Metab Dis 16,639-647[Medline][Order article via Infotrieve]
  17. Linser, PJ, Perkins, M. (1987) Gliogenesis in the embryonic avian optic tectum: neuronal-glial interactions influence astroglial phenotype maturation Dev Brain Res 31,277-290
  18. Fadool, JM, Linser, PJ (1993) 5A11 antigen is a cell recognition molecule which is involved in neuronal-glial interactions in avian neural retina Dev Dyn 196,252-262[Medline][Order article via Infotrieve]
  19. Neil, JM, Barnstable, C. (1990) Expression of the surface antigens RET-PE2 and N-CAM by rat retinal pigment epithelial cells during development and in tissue culture Exp Eye Res 51,573-583[Medline][Order article via Infotrieve]



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