| First Author | Smith SB | Year | 1995 |
| Journal | Mouse Genome | Volume | 93 |
| Issue | 3 | Pages | 871-3 |
| Mgi Jnum | J:28910 | Mgi Id | MGI:76448 |
| Citation | Smith SB, et al. (1995) Slow progressive loss of photoreceptor cells in vitiligo mice co-segregates with gradual depigmentation of the pelage. Mouse Genome 93(3):871-3 |
| abstractText | Full text of Mouse Genome contribution: SLOW PROGRESSIVE LOSS OF PHOTORECEPTOR CELLS IN VITILIGO MICE COSEGREGATES WITH GRADUAL DEPIGMENTATION OF THE PELAGE. Sylvia B. Smith(1, 2) and Doris J. McCool(1), Department of Cellular Biology and Anatomy1 and Department of Ophthalmology2, Medical College of Georgia, Augusta, GA 30912-2000. Introduction The vitiligo mouse has a slow progressive loss of photoreceptor cells (1,2) as well as altered coat coloration resulting in white spotting and progressive depigmentation of fur (3). The defect maps to the microphthalmia (mi) locus of chromosome6 (4,s). Of the more than 10 allelic variations reported at the mi locus, many demonstrate a reduced eye size, hence the term microphthalmia (6). The vitiligo mouse eye is of normal size. It is not known whether the gradual photoreceptor cell loss reported for homozygotes co-seferegates with the coat color defect. To address this question, F2 mice produced by an o~tcrosslbackcrossb reeding of mf/mf* with Mus spretus mice were examined for coat color characteristics and retinal phenotype. Materials and methods Animals: C57BL/6-mz*/mP mice were the offspring from our colony of breeding pairs. Mus spretus (+I+) mice were obtained from Jackson Laboratories, Bar Harbor ME. In the initial breeding phase, mza/mi* females were bred with mus spretus males. In the second breeding phase, the female offspring from the initial mating were bred with male mz*/mP mice. The characteristics of coat color and retinal phenotype were analyzed in 74 offspring of the backcross mating. Coat color analysis: Prior to killing, the coat color characteristics were recorded for each animal. The range of coat color was from black (non-agouti) to agouti to gray. In addition, the presence of white spots on the back or belly was noted for each mouse. Histological processing and microscopic analysis: The offspring of the backcross mating (ages 2 - 23 weeks) were killed by C02 and eyes were removed aqd processed as described (1,2). Eyes of Mus spretus mice were also examined for degenerative retinopathy and no atypical retinal morphology was detected (data not shown). Morphometric analysis involved determining the number of rows of photoreceptor cell nuclei at 8 points along the retina. Eyes were examined for: macrophages in the subretinal space, disrupted outer segments separated from the WE, and uneven pigmentation of WE and choroid. These are hallmarks of the retinopathy of homozygote mfi'/mt!i' mice (1,7). Analysis of slides was done in a masked fashion so that the coat color characteristics of a given mouse were not known to the investigator. Only after all data from retina measurements had been collected was the "code" broken and the retinal phenotype compared with the coat color phenotype. Results 36 of 74 mice had uniform fur color with no depigmentation of pelage. Coat color in these animals was either non-agouti (black) or agouti. 38 of 74 mice had fur that was either non-agouti or agouti but also had multiple white patches andlor progressive graying of fur. After systematic examination of retinas, decoding revealed that mice with uniform coat coloration had a normal retinal phenotype. Mice with multiple white spots, graying and/or depigmenting fur had abnormal retinal morphology reminiscent of the homozygous vitiligo mice. Moreover, the retinal pathology worsened progressively with age as shown in Table 1 and Figure 1. Table 1 provides a tabulation of the mice with and without observable retinal pathology. The type of pathology (macrophages in the subretinal space, uneven RPE pigmentation and disrupted outer segments) is also indicated. It is clear that with increasing age, the three pathologic features become more prevalent. In all cases examined, retinal phenotype was the same for both eyes. Table 1. Number of mice with and without retinal pathology (RP*). age (wks): 2; -RP*: 3; +RP: 4; Pathologic features**: macrophages: 4; uneven RPE: 1; disrupted ROS: 0. age (wks): 4; -RP*: 5; +RP: 3; Pathologic features**: macrophages: 3; uneven RPE: 2; disrupted ROS: 2. age (wks): 6; -RP*: 2; +RP: 4; Pathologic features**: macrophages: 3; uneven RPE: 4; disrupted ROS: 3. age (wks): 9-10; -RP*: 8; +RP: 6; Pathologic features**: macrophages: 6; uneven RPE: 3; disrupted ROS: 3. age (wks): 12-14; -RP*: 4; +RP: 6; Pathologic features**: macrophages: 6; uneven RPE: 6; disrupted ROS: 6. age (wks): 16-17; -RP*: 4; +RP: 4; Pathologic features**: macrophages: 4; uneven RPE: 4; disrupted ROS: 4. age (wks): 20; -RP*: 6; +RP: 9; Pathologic features**: macrophages: 9; uneven RPE: 8; disrupted ROS: 9. age (wks): 23; -RP*: 4; +RP: 2; Pathologic features**: macrophages: 2; uneven RPE: 2; disrupted ROS: 2. **Within the subgroup of animals that demonstrated retinal pathology, at least one of three pathologic features were observed: macrophage-like cells in the subretinal space (SRS), uneven pigmentation of the retinal pigment epithelium (RPE) or disruption of the rod outer segments. Figure 1 Legend. Figure 1 shows that in mice possessing the depigmenting pelage, the number of rows of photoreceptor cells was lost at a rate of about one row per month which is the rate reported for homozygous mice (1). In mice with a uniform coat color, the number of rows of photoreceptors was maintained at about 9-10 over the period studied. Data for the two groups differed significantly (p=0.00001, ANOVA, two-way, F=9.73, factors: age and group). Discussion The purpose of this study was to determine if the slow progressive retinal degeneration in the vitiligo mouse co-segregates with its coat color abnormalities. The results suggest that it does. It is predicted that 50% or 37 animals should have a depigmenting coat and 50% should have a vitiligo-like retina. 38 mice (51.38 %) had these features. Furthermore, the two phenotypes co-segregated. Only mice with the peculiar coat color trait of depigmentation/white spotting had abnormal retinas. Mice with uniform coloration did not. Although many mice with microphthalmia (mi) mutations have small eyes, a slow degenerative retinopathy has not been reported for any except the vitiligo (mivit/mivit) mouse. It had not been determined whether this retinopathy was mediated by a gene closely linked to the gene mediating the pelage depigmentation or whether both characteristics were due to the point mutation at bp793 (8) in the mi gene reported recently as basic helix- loop-helix DNA transcription factor (9, 10). The determination that two phenotypes are mediated by the same gene requires thousands of mice (11) which far exceeds the number analyzed in the present study. Nevertheless, the present study does provide careful analysis of retinal phenotype and coat coloration and the data are suggestive of phenotypic linkage. These results support investigations of the altered transcription factor in determining the pathogenesis of the mivit/mivit photoreceptor cell degeneration. Acknowledgement Supported by NEI grant EY09682 and an unrestricted grant from Research to Prevent Blindness awarded to the Dept. of Ophthalmology, Medical College of Georgia. The C57BL/6-mivit/mivit breeding pairs were provided by Dr. R.L. Sidman, New Eng. Reg. Primate Res. Ctr., Southboro, MA (colony supported by NEI grant EY 06859). References 1. Smith, SB. (1992) Exp. Eye Res. 55, 903-910. 2. Smith SB, Cope BK, McCoy JR. (1994) Exp. Eye Res. 58, 77-84.2. 3. Lerner AB, Shiohara T, Boissy RE, Jacabson KA, Lamoreux ML, and Moellmann GE. (1986) J. Invest. Dermatol. 87, 299-304. 4. Lamoreux ML, Boissy RE, Womack JE, Nordlund JJ, (1992) J. Hered. 83, 435-439. 5. Tang M, Neumann PE, Kosaras B, Taylor BA, and Sidman RL. (1992) Mouse Genome, 90, 441-443. 6. Green MC. (1989) In: Genetic variants and strains of the laboratory mouse. M.F. Lyon and AG Searle, eds. (New York: Oxford University Press) pp. 12-403. 7. Boissy RE, Moellmann GE, Lemer AB. (1987) Am. J. Pathol. 127, 380-388. 8. Steingrimsson EK, Moore J, Lamoreux ML, et al (1994) Nature Genetics 8:256-263. 9. Hodgkinson CA, Moore KJ, Nakayama A, et al (1993) Cell, 74, 395-404. 10. Hughes MJ, Lingrel JB, Krakowsky JM, and Anderson KP. (1993) J. Biol. Chem. 268, 20687-20690. 11. Green MC. (1981) Genetics and probability in breeding experiments. (New York: MacMillan Publishers) |
