Cre-mediated gene deletion in the mammary gland.

To delete genes specifically from mammary tissue using the Cre-lox system, we have established transgenic mice expressing Cre recombinase under control of the WAP gene promoter and the MMTV LTR. Cre activity in these mice was evaluated by three criteria. First, the tissue distribution of Cre mRNA was analyzed. Second, an adenovirus carrying a reporter gene was used to determine expression at the level of single cells. Third, tissue specificity of Cre activity was determined in a mouse strain carrying a reporter gene. In adult MMTV-Cre mice expression of the transgene was confined to striated ductal cells of the salivary gland and mammary epithelial cells in virgin and lactating mice. Expression of WAP-Cre was only detected in alveolar epithelial cells of mammary tissue during lactation. Analysis of transgenic mice carrying both the MMTV-Cre and the reporter transgenes revealed recombination in every tissue. In contrast, recombination mediated by Cre under control of the WAP gene promoter was largely restricted to the mammary gland but occasionally observed in the brain. These results show that transgenic mice with WAP-Cre but not MMTV-Cre can be used as a powerful tool to study gene function in development and tumorigenesis in the mammary gland.

[1]  G. Eichele,et al.  Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2 , 1997, Nature.

[2]  K. Wassarman,et al.  Zp3–cre, a transgenic mouse line for the activation or inactivation of loxP-flanked target genes specifically in the female germ line , 1997, Current Biology.

[3]  P. Gruss,et al.  Temporal control of the Cre recombinase in transgenic mice by a tetracycline responsive promoter. , 1996, Nucleic acids research.

[4]  L. Hennighausen,et al.  Time-Sensitive Reversal of Hyperplasia in Transgenic Mice Expressing SV40 T Antigen , 1996, Science.

[5]  J. Rossant,et al.  The Tumor Suppressor Gene Brca1 Is Required for Embryonic Cellular Proliferation in the Mouse , 1996, Cell.

[6]  L. Hennighausen,et al.  Conditional gene expression in secretory tissues and skin of transgenic mice using the MMTV‐LTR and the tetracycline responsive system , 1995, Journal of cellular biochemistry.

[7]  S. Sugano,et al.  Efficient gene activation in mammalian cells by using recombinant adenovirus expressing site-specific Cre recombinase. , 1995, Nucleic acids research.

[8]  M Aguet,et al.  Inducible gene targeting in mice , 1995, Science.

[9]  L. Hennighausen,et al.  Mammary epithelial cells undergo secretory differentiation in cycling virgins but require pregnancy for the establishment of terminal differentiation. , 1995, Development.

[10]  K. Rajewsky,et al.  A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells. , 1995, Nucleic acids research.

[11]  M. Gossen,et al.  Temporal control of gene expression in transgenic mice by a tetracycline-responsive promoter. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[12]  L. Hennighausen,et al.  Whey acidic protein extrinsically expressed from the mouse mammary tumor virus long terminal repeat results in hyperplasia of the coagulation gland epithelium and impaired mammary development. , 1994, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[13]  J. Marth,et al.  Tissue- and site-specific DNA recombination in transgenic mice. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[14]  B. Mosinger,et al.  Targeted oncogene activation by site-specific recombination in transgenic mice. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[15]  L. Hennighausen,et al.  The variability in activity of the universally expressed human cytomegalovirus immediate early gene 1 enhancer/promoter in transgenic mice. , 1991, Nucleic acids research.

[16]  B. Groner,et al.  Lactogenic hormone and cell type-specific control of the whey acidic protein gene promoter in transfected mouse cells. , 1991, Molecular endocrinology.

[17]  L. Hennighausen,et al.  Expression of a whey acidic protein transgene during mammary development. Evidence for different mechanisms of regulation during pregnancy and lactation. , 1991, The Journal of biological chemistry.

[18]  L. Hennighausen,et al.  Comparison of the regulation of the whey acidic protein gene with that of a hybrid gene containing the whey acidic protein gene promoter in transgenic mice. , 1988, Molecular endocrinology.

[19]  L. Hennighausen,et al.  A milk protein gene promoter directs the expression of human tissue plasminogen activator cDNA to the mammary gland in transgenic mice. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[20]  P. Leder,et al.  Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene , 1988, Cell.

[21]  B. Sauer,et al.  Functional expression of the cre-lox site-specific recombination system in the yeast Saccharomyces cerevisiae. , 1987, Molecular and cellular biology.

[22]  P. Leder,et al.  Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice: Synergistic action of oncogenes in vivo , 1987, Cell.

[23]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[24]  B. Groner,et al.  Ha-ras oncogene expression directed by a milk protein gene promoter: tissue specificity, hormonal regulation, and tumor induction in transgenic mice. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[25]  A. E. Sippel,et al.  Comparison of the whey acidic protein genes of the rat and mouse. , 1984, Nucleic acids research.

[26]  N. Sternberg,et al.  Bacteriophage P1 site-specific recombination. I. Recombination between loxP sites. , 1981, Journal of molecular biology.