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http://dx.doi.org/10.5487/TR.2008.24.1.069

Studies on the Small Body Size Mouse Developed by Mutagen N-Ethyl-N-nitrosourea  

Zhang, Qian-Kun (Department of Research & Development, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology)
Cho, Kyu-Hyuk (Department of Research & Development, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology)
Cho, Jae-Woo (Department of Research & Development, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology)
Cha, Dal-Sun (Department of Research & Development, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology)
Park, Han-Jin (Department of Research & Development, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology)
Yoon, Seok-Joo (Department of Research & Development, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology)
Zhang, ShouFa (Department of Veterinary Medicine, YanBian University)
Song, Chang-Woo (Department of Research & Development, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology)
Publication Information
Toxicological Research / v.24, no.1, 2008 , pp. 69-78 More about this Journal
Abstract
Mutant mouse which show dwarfism has been developed by N-ethyl-N-nitrosourea (ENU) mutagenesis using BALB/c mice. The mutant mouse was inherited as autosomal recessive trait and named Small Body Size (SBS) mouse. The phenotype of SBS mouse was not apparent at birth, but it was possible to distinguish mutant phenotype from normal mice 1 week after birth. In this study, we examined body weight changes and bone mineral density (BMD), and we also carried out genetic linkage analysis to map the causative gene(s) of SBS mouse. Body weight changes were observed from birth to 14 weeks of age in both affected (n = 30) and normal mice (n = 24). BMD was examined in each five SBS and normal mice between 3 and 6 weeks of age, respectively. For the linkage analysis, we produced backcross progeny [(SBS${\times}$C57BL/6J) $F_1{\times}$ SBS] $N_2$ mice (n = 142), and seventy-four microsatellite markers were used for primary linkage analysis. Body weight of affected mice was consistently lower than that of the normal mice, and was 43.7% less than that of normal mice at 3 weeks of age (P < 0.001). As compared with normal mice at 3 and 6 weeks of age, BMD of the SBS mice was significantly low. The results showed 15.5% and 14.1 % lower in total body BMD, 15.3% and 8.7% lower in forearm BMD, and 29.7% and 20.1% lower in femur BMD, respectively. The causative gene was mapped on chromosome 10. The map order and the distance between markers were D10Mit248 - 2.1 cM - D10Mit51 - 4.2 cM - sbs - 0.7 cM - D10Mit283 - 1.4cM - D10Mit106 - 11.2cM - D10Mit170.
Keywords
Small body size mice; Linkage analysis; Body weight; Bone mineral density;
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1 Brown, S.D.M. and Hardisty, R.E. (2003). Mutagenesis strategies for identifying novel loci associated with disease phenotypes. Semin. Cell Dev. Biol., 14, 19-24   DOI   ScienceOn
2 Cheverud, J.M., Routman, E.J., Duarte, F.A., van Swinderen, B., Cothran, K. and Perel, C. (1996). Quantitative trait loci for murine growth. Genetics, 142, 1305-1319
3 Deng, H.W. and Recker, R.R. (2004). Gene mapping and identification for osteoporosis. J. Musculoskelet. Neuronal Interact., 4, 91-100
4 Drake, T.A., Schadt, E., Hannani, K. and Lusis, A.J. (2001). Genetic loci determining bone density in mice with dietinduced atherosclerosis. Physiol. Genom., 5, 205-215   DOI
5 Duncan, E..L, Brown, M.A., Sinsheimer, J., Bell, J., Carr, A.J., Wordsworth, B.P. and Wass, J.A. (1999). Suggestive linkage of the parathyroid receptor type 1 to osteoporosis. J. Bone Miner. Res., 14, 1993-1999   DOI   ScienceOn
6 Hu, C.T. and O'shaughnessy, K.M. (2001). Glycerol-enhanced mini-polyacrylamide gel electrophoresis for the separation of differentially expressed DNA fragments in cDNA representational difference analysis. Electrophoresis, 22, 1063-1068   DOI   ScienceOn
7 Justice, M.J. and Bode, V.C. (1986). Induction of new mutations in a mouse t-haplotype using ethylnitrosourea mutagenesis. Gene Res., 47, 187-192   DOI   ScienceOn
8 Justice, M.J., Noveroske, J.K., Weber, J.S., Zheng, B. and Bradley, A. (1999). Mouse ENU mutagenesis. Hum. Mol. Genetics, 8, 1955-1963   DOI   ScienceOn
9 Justice, M.J., Carpenter, D.A., Favor, J., Neuhauser, K.A., Hrabe de Angelis, M., Soewarto, D. and Bode, V.C. (2000). Effects of ENU doseage on mouse strains. Mamm. Genome, 11, 484-488   DOI   ScienceOn
10 Kim, J.C., Shin, D.H., Kim, S.H., Yang, Y.S., Oh, K.S., Jiang, C.Z. and Chung, M.K. (2006). Teratogenicity evaluation of 2-bromopropane using rat whole embryo culture. J. Toxicol. Pub. Health, 22, 127-133   과학기술학회마을
11 Kwack, S.J. and Cho, D.H. (2005). The recommended approaches and recent trends in reproductive and developmental toxicology. J. Toxicol. Pub. Health, 21, 271-278   과학기술학회마을
12 Purdue, P.E., Zhang, J.W., Skoneczny, M. and Lazarow, P.B. (1997). Rhizomelic chondrodysplasia punctata is caused by deficiency of human PEX7, a homologue of the yeast PTS2 receptor. Nat. Genet., 15, 381-384   DOI   ScienceOn
13 Russel, W.L., Kelly, E.M., Hunsicker, P.R., Bangham, J.W., Maddux, S.C. and Phipps, E.L. (1979). Specific-locus test shows ethylnitrosourea to be the most potent mutagen in the mouse. Proc. Matl. Acad. Sci., 76, 5818-5819
14 Takeuchi, T., Suzuki, H., Sakurai, S., Nogami, H., Okuma, S. and Ishikawa, H. (1990). Molecular mechanism of growth hormone (GH) deficiency in the spontaneous dwarf rat: detection of abnormal splicing of GH messenger ribonucleic acid by polymerase chain reaction. Endocrinology, 126, 31-38   DOI   ScienceOn
15 Braga, V., Sangalli, A., Malerba, G., Mottes, M., Mirandola, S., Gatti, D., Rossini, M., Zamboni, M. and Adami, S. (2002). Relationship among VDR (BsmI and FokI), COLIA1, and CTR polymorphisms with bone mass, bone turnover markers, and sex hormones in men. Calcif. Tissue Int., 70, 457-462   DOI   ScienceOn
16 Waterston, R.H., Lindblad-Toh, K., Birney, E., Rogers, J., Abril, J.F., Agarwal, P., Agarwala, R. and Mouse Genome sequencing Consortium (2002). Initial sequencing and comparative analysis of the mouse genome. Nature, 420, 520-562   DOI   ScienceOn
17 WHO (1994). Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. World Health Organ Tech. Report Series No. 843, Geneva: WHO, 1-129
18 Godfrey, P., Rahal, J.O., Beamer, W.G., Copeland, N.G., Jenkins, N.A. and Mayo, K.E. (1993). GHRH receptor of little mice contains a missense mutation in the extracellular domain that disrupts receptor function. Nat. Genet., 4, 227-232   DOI   ScienceOn
19 Lin, S.C., Lin, C.R., Gukovsky, I., Lusis, A.J., Sawchenco, P.E. and Rosenfeld, M.G. (1993). Molecular basis of the little mouse phenotype and implications for cell-type specific growth. Nature, 364, 209-214
20 Lira, S.A., Kalla, K.A., Glass, C.K., Drolet, D.W. and Rosenfeld, M.G. (1993). Synergistic interactions between Pit-1 and other elements are required for effective somatotroph rat growth hormone gene expression in transgenic mice. Mol. Endocrinol., 7, 694-701   DOI   ScienceOn
21 Wynne, F., Drummond, F., O'Sullivan, K., Daly, M., Shanahan, F., Molloy, M.G. and Quane, K.A. (2002). Investigation of the genetic influence of the OPG, VDR (Fok1), and COLIA1 Sp1 polymorphisms on BMD in the Irish population. Calcif. Tissue Int., 71, 26-35   DOI   ScienceOn
22 Hitotsumachi, S., Carperter, D.A. and Russel, W.L. (1985). Dose repetition increases the mutagenic effectiveness of N-ethyl-N-nitrosourea in mouse spermatogonia. Proc. Matl. Acad. Sci., 82, 6619-6621
23 Meyer, C.W., Korthaus, D., Jagla, W., Cornali, E., Grosse, J., Fuchs, H., Klingenspor, M., Roemheld, S., Tschop, M., Heldmaier, G., De Angelis, M.H. and Nehls, M. (2004). A novel missense mutation in the mouse growth hormone gene causes semidominant dwarfism, hyperghrelinemia, and obesity. Endocrinology, 145, 2531-2541   DOI   ScienceOn
24 Sornson, M.W., Wu, W. and Dasen, J.S. (1996). Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism. Nature, 384, 327-333   DOI   ScienceOn
25 Beamer, W.G., Shultz, K.L., Donahue, L.R. and Rosen, C.J. (2001). Quantitative trait loci for femoral and lumbar vertebral bone mineral density in C57BL/6J and C3H/HeJ inbred strains of mice. J. Bone Miner. Res., 16, 1195-1206   DOI   ScienceOn
26 Cho, J.W., Yoo, J.K., Cho, K.H., Han, S.S. and Song, C.W. (2003). The Devlopment of Dwarfism Mice Using ENU Mutagenesis. Kor. J. Lab. Ani. Sic., 19, 65-69
27 Soewarto, D., Fella, C., Teubner, A., Rathkolb, B., Pargent, W., Heffner, S. and Angelis, M.H. (2000). The large-scale Munich ENU-mouse-mutagenesis screen. Mamm. Genome, 11, 507-510   DOI   ScienceOn
28 Dietrich, W.F., Miller, J., Steen, R., Merchant, M.A., Damron-Boles, D., Husain, Z., Dredge, R., Daly, M.J., Ingalls, K.A. and O'Connor, T.J. (1996). A comprehensive genetic map of the mouse genome. Nature, 380, 149-152   DOI   ScienceOn
29 Klein, R.F., Mitchell, S.R., Phillips, T.J., Belknap, J.K. and Orwoll, E.S. (1998). Quantitative trait loci affecting peak bone mineral density in mice. J. Bone Miner. Res., 13, 1648-1656   DOI   ScienceOn
30 Li, S., Crenshaw III, E.B., Rawson, E.J., Simmonds, D.M., Swanson, L.V. and Rosenfeld, M.G. (1990). Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1. Nature, 347, 528-533   DOI   ScienceOn
31 Russel, W.L., Hunsicker, P.R., Carpenter, D.A., Cornett, C.V. and Guinn, G.M. (1982a). Effect of dose fractionation on the ethylnitrosourea induction of specificlocus mutations in mouse spermatogonia. Proc. Matl. Acad. Sci., 79, 3589-3591
32 Klein, R.F., Carlos, A.S., Vartanian, K.A., Chambers, V.K. and Orwoll, E.S. (2001). Confirmation and fine mapping of chromosomal regions influencing peak bone mass in mice. J. Bone Miner. Res., 16, 1953-1961   DOI   ScienceOn
33 Brites, P., Motley, A.M., Gressens, P., Mooyer, P.A., Ploegaert, I., Everts, V., Evrard, P., Carmeliet, P., Dewerchin, M., Schoonjans, L., Duran, M., Waterham, H.R., Wanders, R.J. and Baes, M. (2003). Impaired neuronal migration and endochondral ossification in Pex7knockout mice: a model for rhizomelic chondrodysplasia punctata. Hum. Mol. Genet., 12, 2255-2267   DOI   ScienceOn
34 Davis, A.P., Woychik, R.P. and Justice, M.J. (1999). Effective chemical mutagenesis in FVB/N mice requires low dose s of ethylnitrosourea. Mamm. Genome, 10, 308-310   DOI
35 Shibayama, K., Ohyama, Y., Ono, M. and Furudate, S. (1993). Expression of mRNA coding for pituitary hormones and pituitary-specific transcription factor in the pituitary gland of the rdw rat with hereditary dwarfism. J. Endocrinol., 138, 307-313   DOI   ScienceOn
36 Shimizu, M., Higuchi, K., Kasai, S., Nakamura, T. and Hosokawa, M. (2001). Chromosome 13 locus, Pbd2, regulates bone density in mice. J. Bone Miner. Res., 12, 1972-1982
37 Deng, H.W., Shen, H., Xu, F.H., Deng, H.Y., Conway, T., Zhang, H.T. and Recker, R.R. (2002). Tests of linkage and/or association of genes for vitamin D receptor, osteocalcin, and parathyroid hormone with bone mineral density. J. Bone Miner. Res., 17, 678-686   DOI   ScienceOn
38 Benes, H., Weinstein, R.S., Zheng, W., Thaden, J.J. and Shmookler, R.R.J. (2000). Chromosomal mapping of osteopenia-associated quantitative trait loci using closely related mouse strains. J. Bone Miner. Res., 15, 626-633   DOI
39 Russel, W.L., Hunsicker, P.R., Raymer, G.D., Steele, M.H., Stelzmer, K.F. and Thompson, H.M. (1982b). Doseresponse curve for the ethylnitrosourea-inducted specificlocus mutations in mouse spermatogonia. Proc. Matl. Acad. Sci., 79, 3589-3591
40 Braverman, N., Steel, G., Obie, C., Moser, A., Moser, H., Gould, S.J. and Valle, D. (1997). Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata. Nat. Genet., 15, 369-376   DOI   ScienceOn
41 Noveroske, J.K., Weber, J.S. and Justice, M.J. (2000). The mutagenic action of ENU in the mouse. Mamm. Genome, 11, 478-483   DOI   ScienceOn
42 Jansson, J.O., Downs, T.R., Beamer, W.G. and Frohman, L.A. (1986). Receptor-associated resistance to growth hormonereleasing factor in dwarf 'little' mice. Science, 232, 511-512   DOI
43 Argentin, G. and Cicchetti, R. (2000). In vitro proliferation of achondroplastic and normal mouse chondrocytes, before and after basic fibroblast growth factor stimulation. Cell Prolif., 33, 397-405   DOI   ScienceOn
44 Beamer, W.G., Shultz, K.L., Churchill, G.A. and Donahue, L.R. (1999). Quantitative trait loci for bone density in C57BL/6J and CAST/EiJ inbred mice. Mamm. Genome., 10, 1043-1049   DOI
45 Lander, E.S., Linton, L.M., Birren, B., Nusbaum, C., Zody, M.C., Baldwin, J., Devon, K., Dewar, K. and Wyman, D. (2001). Initial sequencing and analysis of the human genome. Nature, 409, 860-921   DOI   ScienceOn
46 Rosen, C.J., Beamer, W.G. and Donahue, L.R. (2001). Defining the genetics of osteoporosis: Using the mouse to understand man. Osteoporos. Int., 12, 803-810   DOI
47 Shelovsky, A., McDonald, J.D., Symula, D.M. and Dove, W.F. (1993). Mouse models of human phenylketonuria. Genetics, 134, 1205-1210
48 Hrabe de Angelis, M.H., Flaswinkel, H., Fuchs, H., Balling, R. and Balling, R. (2000). Genome-wide, large-scale production of mutant mice by ENU mutagenesis. Nat. Genet., 25, 444-447   DOI   ScienceOn
49 Hwang, Q.Y., Recker, R.R. and Deng, H.W. (2003). Searching for osteoporosis genes in the post-genome era: progress and challenges. Osteoporos. Int., 14, 701-715   DOI
50 Masinde, G.L., Li, X., Gu, W., Wergedal, J., Mohan, S. and Baylink, D.J. (2002). Quantitative trait loci for bone density in mice: the genes determining total skeletal density and femur density show little overlap in F2 mice. Calcif. Tissue Int., 71, 421-428   DOI
51 Purchase, I.F.H. (2001). Assessment of the risk of exposure to chemical carcinogens. J. Toxicol. Pub. Health, 17, 41-45
52 Ressell, L.B. and Russell, W.L. (1992). Frequency and nature of specific-locus mutations induced in female mice by radiations and chemicals: a review. Mutat. Res., 296, 107-127   DOI   ScienceOn
53 Shimizu, M., Higuchi, K., Bennett, B., Xia, C. and Hosokawa, M. (1999). Identification of peak bone mass QTL in spontaneously osteoporotic mouse strain. Mamm. Genome, 10, 81-87   DOI
54 Wang, Y., Spatz, M.K., Kannan, K., Hayk, H., Avivi, A., Gorivodsky, M., Pines, M., Yayon, A., Lonai, P. and Givol, D. (1999). A mouse model for achondroplasia produced by targeting fibroblast growth factor receptor 3. Proc. Natl. Acad. Sci., 96, 4455-4460
55 Li, X., Masinde, G., Gu, W., Wergedal, J., Mohan, S. and Baylink, D.J. (2002). Genetic dissection of femur breaking strength in a large population (MRL/MpJ x SJL/J) of F2 mice: single QTL effects, epistasis, and pleiotropy. Genomics, 79, 734-740   DOI   ScienceOn
56 Ishikawa, A. and Namikawa, T. (2004). Mapping major quantitative trait loci for postnatal growth in an intersubspecific backcross between C57BL/6J and Philippine wild mice by using principal component analysis. Genes Genet. Syst., 79, 27-39   DOI   ScienceOn
57 Eason, J., Hall, C.M. and Trounce, J.Q. (1995). Renal tubular leakage complicating microcephalic osteodysplastic primordial dwarfism. J. Med. Genet., 32, 234-235   DOI
58 Gibbs, R.A., Weinstock, G.M., Metzker, M.L., Muzny, D.M., Sodergren, E.J., Scherer, S., Scott, G. and Rat Genome Sequencing Project Consortium (2004). Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature, 428, 493-521   DOI   ScienceOn
59 Tsuji, T. and Kunieda, T. (2005). A loss-of-function mutation in natriuretic peptide receptor 2 (Npr2) gene is responsible for disproportionate dwarfism in cn/cn mouse. J. Biol. Chem., 280, 14288-14292   DOI   ScienceOn
60 Zhou, X., Benson, K.F., Ashar, H.R. and Chada, K. (1995). Mutation responsible for the mouse pygmy phenotype in the developmentally regulated factor HMGI-C. Nature, 376, 771-774   DOI   ScienceOn