Abstract
The phenomenon of mosaic expression at the cellular level is frequently observed in tissues and organs of transgenic animals. The report concerns mosaicism in the progeny of five transgenic mouse founders carrying the LacZ reporter gene under the control of 5′-regulatory sequences of bovine and goat alpha-S 1 -casein genes of various sizes. Cells positive for β-galactosidase E. coli activity were detected in lactating mammary glands of all transgenic females; however, the distribution of positive cells within the mammary glands was variable. We observed two types of mosaics, i.e., lobular (clonal) variegation when most or all lobular cells were positive for β-galactosidase and stochastic mosaicism when only single β-galactosidase positive cells were scattered within mammary glands. It is suggested that the stochastic type of mosaicism is realized in cells at the terminal stage of the differentiation of lactating glands, whereas the lobular one is developed from proliferating precursors capable of forming a whole lobule. The ectopic expression of the reporter gene was detected in the mandibular salivary gland in the offspring of two of the five founders No16 and No37, as well as in ovary follicles at the atrezia stage in the progeny of one of these founders. The low level of ectopic expression means that the 5′-flanked regulatory sequences of alpha-S 1 -casein gene of various lengths used in the constructs ensure the reliable tissue-specific expression of the reporter gene.
Similar content being viewed by others
References
Andreeva, L.E. and Serova, I.A., The Effect of the Micromanipulations Used for Transgenosis on Mouse Development, Ontogenez, 1992, vol. 23, no. 6, pp. 637–643.
Biankin, S.A., Collector, M.I., Biankin, A.V., Brown, L.J., Kleeberger, W., Devereux, W.L., Zahnow, C.A., Baylin, S.B., Watkins, D.N., Sharkis, S.J., and Leach, S.D., A Histological Survey of Green Fluorescent Protein Expression in “Green” Mice: Implications for Stem Cell Research, Pathology, 2007, vol. 39, pp. 247–251.
Brinster, R.L., Chen, H.Y., Trumbauer, M.E., Yagle, M.K., and Palmiter, R.D., Factors Affecting the Efficiency of Intro ducing Foreign DNA into Mice by Microinjecting Eggs, Proc. Natl. Acad. Sci. USA, 1985, vol. 82, pp. 4438–4442.
Chrenek, P., Ryban, L., Vetr, H., Makarevich, A.V., Uhrin, P., Paleyanda, R.K., and Binder, B.R., Expression of Recombinant Human Factor VIII in Milk of Several Generations of Transgenic Rabbits, Transgenic Res., 2007, vol. 16, pp. 353–361.
Dobie, K.W., Lee, M., Fantes, J.A., Graham, E., Clark, A.J., Springbett, A., Lathe, R., and McClenaghan, M., Variegated Transgene Expression in Mouse Mammary Gland Is Determined by the Transgene Integration Locus, Proc. Natl. Acad. Sci. USA, 1996, vol. 93, pp. 6659–6664.
Dorer, D.R. and Henikoff, S., Expansions of Transgene Repeats Cause Heterochromatin Formation and Gene Silencing in Drosophila, Cell, 1994, vol. 77, pp. 1–20.
Dvoryanchikov, G.A., Serova, I.A., Andreeva, L.E., Dias, L.P.B., Azevedo, S., and Serov, O.L., Secretion of Biologically Active Human Granulocyte Colony-Stimulating Factor (G-CSF) in Milk of Transgenic Mice, Genetika (Moscow), 2005, vol. 41, no. 10, pp. 1330–1337.
Festenstin, R., Tolaini, M., Corbella, P., Mamalaki, C., Parrington, J., Fox, M., Miliou, A., Jones, M., and Kioussis, D., Locus Control Region Function and Heterochromatin-Induced Position Effect Variegation, Science, 1996, vol. 271, pp. 1123–1125.
Garrick, D., Fiering, S., Martin, D.I.K., and Whitelaw, E., Repeat-Induced Gene Silencing in Mammals, Nature Genet., 1998, vol. 18, pp. 56–59.
Guy, L.G., Kothary, R., and Wall, L., Position Effects in Mice Carrying a LacZ Transgene in cis with the beta-Globin LCR Can Be Explained by a Graded Model, Nucleic Acids Res., 1997, vol. 25, pp. 4400–4407.
Guy, L.G., Kothary, R., De Repentigny, Y., Delvoye, N., Ellis, J., and Wall, L., The beta-Globin Locus Control Region Enhances Transcription of but Does not Confer Position-Independent Expression onto the lacZ Gene in Transgenic Mice, EMBO J., 1996, vol. 15, pp. 3713–3721.
Hennighausen, L. and Robinson, G.W., Think Globally, Act Locally: The Making of a Mouse Mammary Gland, Genes. Dev., 1998, vol. 12, pp. 449–455.
Jakobsson, J., Rosenqvist, N., Thompson, L., Barraud, P., and Lundberg, C., Dynamics of Transgene Expression in a Neural Stem Cell Line Transduced with Lentiviral Vectors Incorporating the cHS4 Insulator, Exp Cell Res., 2004, vol. 298, pp. 611–23.
Krepulat, F., Löhler, J., Heinlein, C., Hermannstädter, A., Tolstonog, G.V., and Deppert, W., Epigenetic Mechanisms Affect Mutant p53 Transgene Expression in WAP-mutp53 Transgenic Mice, Oncogene, 2005, vol. 24, pp. 4645–4659.
Kwaks, T.H., Barnett, P., Hemrika, W., Siersma, T., Sewalt, R.G., Satijn, D.P., Brons, J.F., van Blokland, R., Kwakman, P., Kruckeberg, A.L., Kelder, A., and Otte, A.P., Identification of Ani-repressor Elements That Confer High and Stable Protein Production in Mammalian Cells, Nat. Biotechnol., 2003, vol. 21, pp. 553–558.
Liew, C.G., Draper, J.S., Walsh, J., Moore, H., and Andrews, P.W., Transient and Stable Transgene Expression in Human Embryonic Stem Cells, Stem Cells, 2007, vol. 25, pp. 1521–1528.
Liu, Z., Zhao, C., Fan, B., Dai, Y., Zhao, Z., Wang, L., Zheng, M., Feng, J., Chen, Y., Duan, Y., and Li, N., Variable Expression of Human Lactoferrin Gene in Mice Milk Driven by Its 90 bk Upstream Flanking Sequences, Anim. Biotechnol., 2004, vol. 15, pp. 21–31.
Ma, W., Rogers, K., Zbar, B., and Schmidt, L., Effects of Different Fixatives on beta-Galactosidase Activity, J. Histochem. Cytochem., 2002, vol. 50, pp. 1421–1424.
Manzini, S., Vargiolu, A., Stehle, I.M., Bacci, M.L., Cerrito, M.G., Giovannoni, R., Zannoni, A., Bianco, M.R., Forni, M., Donini, P., Papa, M., Lipps, H.J., and Lavitrano, M., Genetically Modified Pigs Produced with a Nonviral Episomal Vector, Proc. Natl. Acad. Sci. USA, 2006, vol. 103, pp. 17672–17677.
Martin, D.I. and Whitelaw, E., The Vagaries of Variegating Transgenes, Bioessays, 1996, vol. 18, pp. 919–923.
Opsahl, M.L., McClenaghan, M., Springbett, A., Reid, S., Lathe, R., Colman, A., and Whitelaw, C.B., Multiple Effects of Genetic Background on Variegated Transgene Expression in Mice, Genetics, 2002, vol. 160, pp. 1107–1112.
Opsahl, M.L., Springbett, A., Lathe, R., Colman, A., McClenaghan, M., and Whitelaw, C.B., Mono-allelic Expression of Variegating Transgene Locus in the Mouse, Transgenic Res., 2003, vol. 12, pp. 661–669.
Pantano, T., Rival-Gervier, S., Prince, S., Menck-Le Bourhis, C., Maeder, C., Viglietta, C., Houdebine, L.M., and Jolivet, G., In Vitro and in Vivo Effects of a Multimerized Alphas 1-Casein Enhancer on Whey Acidic Protein Gene Promoter Activity, Mol. Reprod. Dev., 2003, vol. 65, pp. 262–268.
Pape, J.R., Skynner, M.J., Allen, N.D., and Herbison, A.E., Transgenics Identify Distal 5′- and 3′-Sequences Specifying Gonadotropin-Releasing Hormone Expression in Adult Mice, Mol. Endocrinol., 1999, vol. 13, pp. 2203–2211.
Park, K.W., Lai, L., Cheong, H.T., Cabot, R., Sun, Q.Y., Wu, G., Rucker, E.B., Durtischi, D., Bonk, A., Samuel, M., Rieke, A., Day, B.N., Murphy, C.N., Carter, D.B., and Prather, R.S., Mosaic Gene Expression in Nuclear Transfer-Derived Embryos and the Production of Cloned Transgenic Pigs from Ear-Derived Fibroblasts, Biol. Reprod., 2002, vol. 66, pp. 1001–1005.
Ramírez, A., Milot, E., Ponsa, I., Marcos-Gutiérrez, C., Page, A., Santos, M., Jorcano, J., and Vidal, M., Sequence and Chromosomal Context Effects on Variegated Expression of Keratin 5/lacZ Constructs in Stratified Epithelia of Transgenic Mice, Genetics, 2001, vol. 158, pp. 341–350.
Ramunas, J., Montgomery, H.J., Kelly, L., Sukonnik, T., Ellis, J., and Jervis, E.J., Real-Time Fluorescence Tracking of Dynamic Transgene Variegation in Stem Cells, Mol Ther., 2007, vol. 15, pp. 810–817.
Ramunno, L., Cosenza, G., Rando, A., Pauciullo, A., Illario, R., Gallo, D., Di Berardino, D., and Masina, P., Comparative Analysis of Gene Sequence of Goat CSN1S1 F and N Alleles and Characterization of CSN1S1 Transcript Variants in Mammary Gland, Gene, 2005, vol. 345, pp. 289–299.
Robertson, G., Garrick, D., Wilson, M., Martin, D.I., and Whitelaw, E., Age-Dependent Silencing of Globin Transgenes in the Mouse, Nucleic Acids Res., 1996, vol. 24, pp. 1465–1471.
Shulz, T.J., Glaubitz, M., Kuhlow, D., Thierbach, R., Birringer, M., Steinberg, P., Pfeiffer, A.F., and Ristow, M., Variable Expression of Cre Recombinase Transgenes Precludes Reliable Prediction of Tissue-Specific Gene Disruption by Tail-Biopsy Genotyping, PLoS ONE, 2007, vol. 2, pp. e1013.
Smith, J.R., Maguire, S., Davis, L.A., Alexander, M., Yang, F., Chandran, S., ffrench-Constant, C., and Pedersen, R.A., Robust, Persistent Transgene Expression in Human Embryonic Stem Cells Is Achieved with AAVS1-Targeted Integration, Stem Cells, 2008, vol. 26, pp. 496–504.
Swenson, E.S., Price, J.G., Brazelton, T., and Krause, D.S., Limitations of Green Fluorescent Protein as a Cell Lineage Marker, Stem Cells, 2007, vol. 25, pp. 2593–2600.
Uusi-Oukari, M., Hyttinen, J-M., Kornonen, V.-P., Vasti, A., Alhonen, L., Janne, O.A., and Janne, J., Bovine S1-Casein Gene Sequences Direct High Level Expression of Human Granulocyte-Macrophage Colony-Stimulating Factor in Milk of Transgenic Mice, Transgenic Res., 1997, vol. 6, pp. 75–84.
Wang, Y., Flemming, B.P., Martin, C.C., Allen, S.R., Walters, J., Oeser, J.K., Hutton, J.C., and O'Brien, R.M., Long-Range Enhancers Are Required to Maintain Expression of the Autoantigen Islet-Specific Glucose-6-Phosphatase Catalytic Subunit-Related Protein in Adult Mouse Islets in Vivo, Diabetes, 2008, vol. 57, pp. 133–141.
Williams, A., Harker, N., Ktistaki, E., Veiga-Fernandes, H., Roderick, K., Tolaini, M., Norton, T., Williams, K., and Kioussis, D., Position Effect Variegation and Imprinting of Transgenes in Lymphocytes, Nucleic Acids Res., 2008, vol. 36, pp. 2320–2329.
Author information
Authors and Affiliations
Corresponding author
Additional information
Original Russian Text © I.A. Serova, L.E. Andreeva, N.V. Khaidarova, L.P.B. Dias, G.A. Dvoryanchikov, I.A. Burkov, N.V. Baginskaya, 2009, published in Tsitologiya, Vol. 51, No. 11, 2009, pp. 972–980.
Rights and permissions
About this article
Cite this article
Serova, I.A., Andreeva, L.E., Khaidarova, N.V. et al. Mosaic expression of LacZ reporter gene controlled by 5′-regulatory sequences of alpha-S 1 -Casein gene in transgenic mice. Cell Tiss. Biol. 3, 409–416 (2009). https://doi.org/10.1134/S1990519X09050022
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S1990519X09050022