| First Author | Frijhoff AFW | Year | 1996 |
| Journal | Mouse Genome | Volume | 94 |
| Issue | 4 | Pages | 866-70 |
| Mgi Jnum | J:38091 | Mgi Id | MGI:85480 |
| Citation | Frijhoff AFW, et al. (1996) Production of a congenic mouse strain carrying the hairless (hr) mutation in a 129/Ola genetic background: a suitable strain to generate transgenic and knockout mice for studies on toxicity and carcinogenesis of skin. Mouse Genome 94(4):866-70 |
| abstractText | PRODUCTION OF A CONGENIC MOUSE STRAIN CARRYING THE HAIRLESS (hr) MUTATION IN A 129/Ola GENETIC BACKGROUND: A SUITABLE STRAIN TO GENERATE TRANSGENIC AND KNOCKOUT MICE FOR STUDIES ON TOXICITY AND CARCINOGENESIS OF SKIN. Anita FW Frijhoff, Sandra AM Bol(a), Peter C Groot(b), Albert A van Zeeland(a), Peter Demant(c) and Robert A Baan; Department of Molecular Toxicology, TNO Nutrition and Food Research Institute, PO Box 5815,2280 HV Rijswijk, (a) MGC-Department of Radiation Genetics and Chemical Mutagenesis, Leiden University, Leiden, (b) Faculty of Veterinary Medicine, Utrecht University, Utrecht and (c) Department of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands. Studies of skin toxicity and carcinogenesis require direct contact of the skin with the agent of interest. However, shaving leads to skin irritation and, furthermore, ultraviolet light (UV) doses given will be attenuated by hair still present in hair follicles. The hairless, immunocompetent, mouse strain SKHl has been shown to be a convenient model for studies of skin carcinogenesis induced by UV or chemicals (1, 2, 3). This mouse develops total alopecia around the age of 3-4 weeks (4, 5) due to disruption of the hairless (hr) locus on chromosome 14 by retroviral insertion (6, 7). By interbreeding the hairless mouse with transgenic/knockout mice, which are widely being generated by gene targeting in embryonic stem (ES) cells derived from 129/Ola mice (reviewed in 8), mouse models can be obtained that allow one to study the role of specific genes in skin toxicity or carcinogenesis. Crossing of hairless SKHl (hr/hr) mice with the hairy (+ /+) transgenic/knockout mice and subsequent interbreeding of their hairy Fl (+/hr) litter will result in F2 progeny part of which are hairless (hr/hr) transgenic/knockout mice. The genetic background of these mice, which plays an important role in carcinogenesis, will however be heterogeneous and different from the hairy (+/+) transgenic/ knockout mice from which they were derived. This will likely hamper the comparison of the results of studies of skin carcinogenesis conducted in the hairless transgenic/ knockout mouse with carcinogenesis studies on organs other than skin in its hairy counterpart. Several studies have shown that susceptibility to tumor formation differs greatly between inbred strains of mice (9, 10). To obviate genetic heterogeneity among hairless transgenic knockout mice, we generated a (semi) congenic strain carrying the hairless mutation in a 129/Ola genetic background, to be used in crosses with -hairy- transgenic/knockout mice which have been generated by gene targeting in 129/Ola ES cells. The hairless 129/Ola inbred mouse strain was generated by crossing female 129/Ola mice with male SKH1 mice, followed by repeated backcrossing to female 129/Ola mice and testing each generation for the presence of the hr allele. This was done by isolating tail-DNA (11), followed by typing with D14Mit8, D14Mit32 and D14Mit41 (Research Genetics, Huntsville, Ala.), essentially as described (12). D14Mit8, D14Mit32 and D14Mit41 are located at 48, 32.5 and 42.5 cM from the centromere and surround the hr allele which is situated at 39.6 cM from the centromere (13). At the time of the experiments the precise location of the hr locus was unknown, therefore these 3 marker loci were used to enhance the reliability of the method. Backcross (BC) mice possessing all three SKH1 alleles (see Fig. 1) were selected and further backcrossed with 129/Ola mice. After 7 backcross-generations (BC7), a homozygous hairless (hr/hr) 129/Ola inbred strain was produced by brother-sister matings of hr-carrying mice. Theoretically, the genetic background of this mouse strain is over 99% 129/Ola. Homozygous hairless (hr/hr) 129/Ola inbred mice are now available for interbreeding with 129/Ola transgenic/knockout mice. Thus, genetically homogeneous hairless transgenic/knockout mice will be obtained in which the role of transgenes/knockouts in skin toxicity and carcinogenesis can be studied in a pure 129/Ola genetic background, thus eradicating confounding factors inherent to genetic heterogeneity. Figure 1. (Legend). Simple sequence length polymorphism of BC7 mice. Lanes marked with an asterisk correspond to BC7 mice which possess the alleles of the SKH1 strain for all markers tested and thus the hr locus. Brother-sister matings of these mice produced the homozygous hairless (hr/hr) 129/Ola inbred strain. ACKNOWLEDGEMENTS This research was supported by the Netherlands Organization for Advancement of Science through the foundation of Medical Scientific Research (contract no. 900-01-093). REFERENCES 1. Forbes PD (1981) In Proceedings of the 2nd NCI/EPA/NIOSH Collaborative Workshop: Progress on joint environmental and occupational cancer studies, Kraybill HF, Blackwood IC, Freas NB (eds.) 1982-3610132:561, US Government Printing Office, pp. 671-684. 2. Gallagher CH, Canfield PJ, Greenoak GE, Reeve VE (1984). J Invest Dermatol, 83:169-174. 3. Poland A, Knutson JC, Glover E (1984) J Invest Dermatol, 83: 454-459. 4. Crew FAE, Mirskaia L (1931) J Genet, 25:17-24. 5. Snell GD (1931) Genetics, 16:42-74. 6. Stoye JP, Fenner S, Greenoak GE, Moran C, Coffin JM (1988) Cell, 54:383-391. 7. Cachon-Gonzalez MB, Fenner S, Coffin JM, Moran C, Best S,, Stoye JP (1994) Proc Natl Acad Sci USA, 91:7717-7721. 8. Melton DW (1994) Bioessays 16:633-638. 9. Demant P, Oomen LC, Oudshoorn-Snoek M (1989) Adv Cancer Res 53:117-179. 10. Drinkwater NR, Bennett LM (1991) Prog Exp Tumor Res, 33: 1-20. 11. Laird PW, Zijderveld A, Linders K, Rudnicki MA, Jaenisch R, Berns A (1991) Nucleic Acids Res, 19:4293. 12. Dietrich W, Katz H, Lincoln SE, Shin H-S, Dracopoli N, Lander ES (1992) Genetics, 131:423-447. 13. Nadeau JH, McCarthy L, Cox R (1994) Mammalian Genome, 5:S207-S216. 14. Dietrich WF, Miller JC, Steen RG, Merchant M, Damron D, Nahf R, Gross A, Joyce DC, Wessel M, Dredge RD et al. (1994) Nat Genet, 7:220-245. |
