| First Author | Kondo T | Year | 1997 |
| Journal | Mouse Genome | Volume | 95 |
| Issue | 3 | Pages | 698-700 |
| Mgi Jnum | J:43274 | Mgi Id | MGI:1097454 |
| Citation | Kondo T, et al. (1997) The "NOA" MOUSE; A NEW HAIR-DEFICIENT MUTANT (A POSSIBLE ANIMAL MODEL OF ALLERGIC DERMATITIS). Mouse Genome 95(3):698-700 |
| abstractText | Full text of Mouse Genome contribution: THE "NOA" MOUSE: A NEW HAIR-DEFICIENT MUTANT (A POSSIBLE ANIMAL MODEL OF ALLERGIC DERMATITIS). Taizo Kondo, Yasuhisa Shiomoto, Toshio Kondo, and Shuji Kubo Naruto Research Institute, Otsuka Pharmaceutical Factory, Inc., 115 Tateiwa, Muya-cho, Naruto, Tokushima 772, Japan Introduction Since Gaskoin (1) described a family of mice with hairless, wrinkled skin which was named "nudoplicatus" in 1856, a number of hereditary hairless or sparsely coated mouse mutants such as hairless (hr/hr) (2) and rhino (hrhr/hrhr) (3) have been reported and have contributed to various biomedical studies. We have discovered a new mutant mouse strain with deficient hair growth and have named it the "NOA" mouse by combining the initials of our institution with the term atrichia (Naruto Research Institute -Otsuka Atrichia). Although this mutant is known to have originated from a male spontaneously sparsely coated mutant obtained in 1982 by cross breeding between a female C3H/He mouse and a male ddY mouse at our facility, its genetic background is unclear because we did not maintain the mutant in systematic breeding. In gross appearance, the NOA mouse becomes completely hairless and smooth-skinned in adulthood until the development of skin lesions as described below. Since 1990, we have been systematically inbreeding these mice by homozygous brother-sister mating under barrier-system conditions to establish a new hairless mouse strain. In addition, because the mice frequently develop ulcerative skin lesions, we have started to look into the possibility of using this mutant as an animal model of allergic or atopic dermatitis. This initial report describes the observed characteristics of this new inbred strain, the "NOA" mouse. Materials and Methods Male NOA mice, which are being inbred at our facility, were compared with HRS/J mice (male, Jackson Laboratories, Bar Harbor, Maine, USA), which are a standard hairless mutant mouse as well as a representative strain of hairless (hr/hr), and further compared with 2 strains of hairy mice (ddY and ICR, male, Japan SLC, Inc., Shizuoka, Japan). In the cross mating study, female ddY mice (Japan SLC, Inc.) were used. The animal facility was under barrier-system conditions, periodically subjected to microbiological monitoring, and confirmed to be free of categories A, B, C, and E of microbes and parasites specified for monitoring in mice and rats by the ICLAS Monitoring Center (Asia) (4). Although HRS/J mice were the only strain bred under conventional conditions, no microbes or parasites except for Pasteurella pneumotropica were detected, and no lesions or clinical signs attributable to P. pneumotropica were observed. The external appearance of the coat and claws in NOA and HRS/J mice was grossly observed daily. In addition, the condition of the skin in NOA mice was grossly observed daily to assess the course of development of ulcerative skin lesions. In the cross mating study, 3 pairs of female ddY and male NOA mice were mated to F1, (first filial generation) and F2 (second filial generation) produced by 6 pairs of F1 brother-sister breeding. The normal dorsal skin of NOA and HRS/J mice and ulcer lesional skin of NOA mice were examined histopathologically. Skin samples were fixed in 10% buffered formalin (pH 7.0), embedded in paraffin in the conventional manner, thin-sectioned, and stained with hematoxylin and eosin (HE) and toluidine blue (TB). In addition, other dorsal skin samples were frozen in liquid nitrogen to prepare fresh frozen sections, which were stained with oil-red-0 and observed under light microscopy. The number of mast cells in the skin of NOA and control animals (HRS/J and hairy mice) was compared not only between individual animals, but also between various skin sites such as the back, lumbar region, chest, and abdomen on TB-stained sliced sections. The number of metachromatic mast cells was counted per linear mm in each skin sample (epidermis to hypodermis), and the mean number of mast cells in the above-mentioned 4 skin sampling sites was compared. With regard to serological examination, serum immunoglobulin E (IgE) levels in NOA and control animals were determined by the sandwich ELISA method using a test kit (MOUSE IgE EIA KIT YAMASA, Yamasa Shoyu Co., Ltd., Chiba, Japan). Results In the NOA mice, curly juvenile hair began to appear thinly over the body as early as the 5th day of age, and there was no growth of pelage hair throughout life. The mice lost their juvenile hair progressively as they matured and became hairless by the 10th week of age. The vibrissae, which were thin and crooked, were lost at around the 12th week of age, and the entire body became completely hairless and smooth-skinned (Fig. 1). In contrast, HRS/J mice continued to grow pelage hair, with some pelage hair persisting in some animals throughout life, and the vibrissae were normal in appearance. The claws in the HRS/J mice were found to overgrow and were twisted or spirally shaped, while these abnormalities were not observed in the NOA mice. In the cross mating study, all Fl mice (15 males and 13 females) were sparsely coated. In F2 mice, three types of coats (hairy, sparse, hairless) were produced in males (6 hairy, 11 sparse, 5 hairless) and females (7 hairy, 10 sparse, 6 hairless). With regard to the ulcerative skin lesions (Fig. 2), such lesions were seen in the NOA mice from the 10th week of age, with prevalence rates of 30% by the 10th week of age and 90% by the 20th week of age (Fig. 3). Specifically, extensive lesions, which developed gradually, were mostly observed from the 16th week of age. In severe cases, the lesions extended to cover almost 20% of the body surface area. Small lesions may resolve spontaneously, but lesions with extensive ulcerative never resolve. Fig. 1. (Legend). Appearance of NOA mouse (10th week of age). Fig. 2. (Legend). Appearance of ulcerative skin lesions of NOA mouse (24th week of age). Histopathologically, there was no evidence of pelage hair formation in the NOA mice, and a number of hair follicle cysts filled with an onion-skin-like mass (eosinophilic) appeared in the hypodermis within a few days after birth and increased in number and size until the 12th week of age (Fig. 4;.TB stain). In the HRS/J mice, pelage hair was produced, but only a few hairs erupted on the skin, with most extending in various directions within the skin tissue, and some cysts were observed in the hair follicles from the 10th week of age. These cysts were of the vacuolar type and filled with an amorphous oil-red-0-positive substance. With regard to the histological findings of the ulcerative skin lesions which developed in the NOA mice, the epidermis showed desquamation, with separation from the basal layer, and the thickness of the dermis increased due to the proliferation of inflammatory cells and collagen bundles. The epidermis adjacent to the ulcerative lesions showed hyperkeratosis, and the stratum spinosum and stratum granulosum were thickened. The most striking histological feature was the presence of large numbers of mast cells in and around the lesions (Fig. 4). Fig. 3. (Legend). Prevalence of ulcerative skin lesions in NOA mice. (n=10 at each age) Fig. 4. (Legend). Histological appearance of skin of NOA mouse. Dorsal skin sample adjacent to an ulcerative lesion from 28 weeks of age. Large numbers of metachromatic mast cells and a number of hair follicle cysts are observed. (TB stain, X 35) Results for the number of mast cells (per linear mm of skin) are shown in Fig. 5. Results for NOA mice were 28.2 (n=10) at the 5th week of age, 24.0 (n=3) at the 20th week of age, and 30.0 (n=2) at the 40th week of age in animals without ulcerative skin lesions, whereas results were 42.6 (n=9) at the 20th week of age and 61.1 (n=9) at the 40th week of age in those with ulcerative skin lesions. Surprisingly, some animals had 300 mast cells or more in and around the lesions. In contrast, the number of mast cells in the control animals (n=5 each) was 15.4 at the 5th week of age, 13.6 at the 20th week of age, and 13.4 at the 40th week of age in the HRS/J mice, with corresponding values of 13.6, 9.4, and 10.8 in the ddY mice and 14.4, 10.6, and 9.8 in the ICR mice. Results for serum IgE levels are shown in Tables 1 and 2. Fig. 5. (Legend). Number of mast cells in skin (per linear mm). NOA:U indicates NOA with ulcerative skin lesions. Table 1. Serum IgE levels (ng/mL) in NOA and hairy mice. Weeks of age: 5; NOA: 122.1 (n=6); NOA:U*: No data; ddY**: 0.0; ICR**: 52.4. Weeks of age: 16; NOA: 385.8 (n=4); NOA:U*: 2,865.2 (n=4); ddY**: 1.7; ICR**: 54.2. Weeks of age: 32; NOA: 456.3 (n=2); NOA:U*: 11,318.1 (n=6); ddY**: 9.2; ICR**: 218.3. *NOA with ulcerative skin lesions. **n=5 at each age Table 2. Serum IgE levels (ng/mL) in HRS/J. Weeks of age: 10; HRS/J*: 127.0. Weeks of age: 20; HRS/J*: 168.0. Weeks of age: 28; HRS/J*: 148.0. *n=5 at each age. Discussion The NOA mouse is distinctly different in external appearance and histological characteristics from the hairless (hr/hr) mouse (HRS/J). With regard to heredity, the hairlessness phenotype of the hairless (hr/hr) mouse is known to be an autosomal recessive gene (5), while the results of a preliminary cross mating study suggest that the hairlessness phenotype of the NOA mouse is an autosomal semidominant gene. Based on their external appearance and histopathological and hereditary characteristics, it may be possible to distinguish the NOA mouse from other known hereditary hairless or sparsely coated mouse mutants (3, 6-13). It is obvious that the NOA mouse has more mast cells than other mouse strains. Furthermore, mast cells were significantly greater in number in NOA mice with ulcerative skin lesions. In particular, most mast cells were observed in and around the ulcerative lesions, suggesting that they play an important role in the development of the lesions. In addition, serological examination showed increased IgE levels in the NOA mouse, with significantly higher levels in those with ulcerative skin lesions, suggesting that IgE may also be involved in the development of the lesions. Based on the results to date, it is expected that the NOA mouse may prove to be a useful animal model of allergic (atopic) dermatitis. Additionally, the NOA mouse may also prove to be a useful model of pruritus because the NOA mouse frequently exhibits scratching behavior suggestive of chronic pruritus. Furthermore, the NOA mouse should have considerable value in studies on type I allergy, on the differentiation and proliferation of mast cells and their functions, on the control mechanisms of IgE production, and on the control of hair growth and loss. In summary, although the relationship between the observed characteristics of the NOA mouse and the development of ulcerative skin lesions, which is the most remarkable characteristic of this new strain, has not yet been clarified, we believe that the NOA mouse is a new type of mutant mouse that is distinguishable from those previously reported. Acknowledgments We would like to thank Dr. Masahisa Kyogoku, Professor Emeritus of Tohoku University, for his helpful comments and suggestions throughout the course of this work. References 1. Gaskoin JS. Proc Zoo1 Soc London 1856; 24:38-40. 2. Brooke HC. J Hered 1926; 17:173-174. 3. Howard A. J Hered 1940; 31:467-470. 4. ICLAS Monitoring Center (Asia). In: Kagiyaina N, ed. Manual of Microbiologic Monitoring of Laboratory Animals. Tokyo: Japanese Society of Laboratory Animals 1988: 4 (in Japanese). 5. Crow FAE. Rep Brit Leeds 1927: 335. 6. Carter TC, et al. J Hered 1950; 41:297-300. 7. Garber ED. J Hered 1952; 43:45-46. 8. Carter TC, et al. J Hered 1954; 45:151-154. 9. Gates AH, et al. Science 1965; 148:1471-1473. 10. Flanagan SP. Genet Res Camb 1966; 8:295-309. 11. Muto H. Medicine and Biology 1967; 75:28-31 (in Japanese). 12. Tsuji S, et al. Jpn J Genetics 1972; 47:297-299. 13. Montagutelli X, et al. J Invest Dermatol 1996; 107:20-25. |
