Homozygous K5Cre transgenic mice have wavy hair and accelerated malignant progression in a murine model of skin carcinogenesis.
Mice with conditional gene deletions have been extremely valuable in allowing investigators to study the genes of interest in a tissue-specific manner. The Cre-loxP recombination system provides a powerful tool to produce targeted rearrangements of particular genes. The keratin 5-Cre recombinase (K5Cre) transgenic mouse line has been used to generate skin specific gene deletions. We found that the K5Cre mice display a unique phenotype when bred to homozygosity. The K5Cre(+/+) mice have a wavy hair coat and curly whiskers. Histologically, the hair follicles appear disoriented. Over time, the K5Cre(+/+) mice develop patches of alopecia. These mice are also runted when compared to wild-type controls. Fostering the K5Cre(+/+) pups to wild-type mothers results in normal weight gain, suggesting a maternal defect in milk production. When the K5Cre(+/+) mammary glands were examined, we not only found a significant decrease in the number of mammary branches in the virgin females, but also a greater number of quiescent alveoli units in the lactating glands. When the K5Cre(+/+) mice were bred to v-Ha-ras (Tg . AC) transgenic mice, the resulting Tg . AC(+/-) K5Cre(+/+) offspring were utilized in a chemically induced skin carcinogenesis model. The mice were treated with 2.5 microg of 12-O-tetradecanoylphorbol-13-acetate (TPA) weekly for 10 wk. No difference was observed in the time to onset of papilloma formation, the number of papillomas and the average papilloma volume between the Tg . AC(+/-) K5Cre(+/+) mice and their corresponding controls. Surprisingly, however, the K5Cre(+/+) papillomas displayed an accelerated tendency to malignant progression; in addition, the frequency of malignant transformation of the papillomas is significantly enhanced. Although the K5Cre(+/+) mice resemble waved-1 and -2 mutants, the molecular basis for the K5Cre(+/+) phenotype is probably different. In conclusion, we discovered a unique phenotype associated with the K5Cre(+/+) transgenic line.
Chan
Edward L
EL
Division of Pediatric Hematology/Oncology, State University of New York at Stony Brook, Stony Brook, New York, USA.
Peace
Belinda E
BE
Toney
Kenya
K
Kader
Sarah A
SA
Pathrose
Peterson
P
Collins
Margaret H
MH
Waltz
Susan E
SE
D000505:Alopecia / Q000473:pathology; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002471:Cell Transformation, Neoplastic; D003043:Cocarcinogenesis; D004249:DNA Damage; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D011905:Genes, ras; D005838:Genotype; D006197:Hair / Q000002:abnormalities*; D018859:Hair Follicle / Q000473:pathology; D006720:Homozygote; D019426:Integrases / Q000378:metabolism*; D053569:Keratin-15; D053555:Keratin-5 / Q000235:genetics / Q000502:physiology*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D008321:Mammary Glands, Animal / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics*; D011995:Recombination, Genetic; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
D002273:Carcinogens; D053569:Keratin-15; D053555:Keratin-5; C492053:Krt15 protein, mouse; C045073:Cre recombinase; D019426:Integrases; D013755:Tetradecanoylphorbol Acetate