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. 1991 Oct;11(10):5154–5163. doi: 10.1128/mcb.11.10.5154

Retrovirus-induced insertional mutagenesis: mechanism of collagen mutation in Mov13 mice.

D D Barker 1, H Wu 1, S Hartung 1, M Breindl 1, R Jaenisch 1
PMCID: PMC361539  PMID: 1922037

Abstract

The Mov13 mouse strain carries a mutation in the alpha 1(I) procollagen gene which is due to the insertion of a Moloney murine leukemia provirus into the first intron. This insertion results in the de novo methylation of the provirus and flanking DNA, the alteration of chromatin structure, and the transcriptional inactivity of the collagen promoter. To address the mechanism of mutagenesis, we reintroduced a cloned and therefore demethylated version of the Mov13 mutant allele into mouse fibroblasts. The transfected gene was not transcribed, indicating that the transcriptional defect was not due to the hypermethylation. Rather, this result strongly suggests that the mutation is due to the displacement or disruption of cis-acting regulatory DNA sequences within the first intron. We also constructed a Mov13 variant allele containing a single long terminal repeat instead of the whole provirus. This construct also failed to express mRNA, indicating that the Mov13 mutation does not revert by provirus excision as has been observed for other retrovirus-induced mutations.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Berk A. J., Sharp P. A. Sizing and mapping of early adenovirus mRNAs by gel electrophoresis of S1 endonuclease-digested hybrids. Cell. 1977 Nov;12(3):721–732. doi: 10.1016/0092-8674(77)90272-0. [DOI] [PubMed] [Google Scholar]
  2. Bornstein P., McKay J., Liska D. J., Apone S., Devarayalu S. Interactions between the promoter and first intron are involved in transcriptional control of alpha 1(I) collagen gene expression. Mol Cell Biol. 1988 Nov;8(11):4851–4857. doi: 10.1128/mcb.8.11.4851. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bornstein P., McKay J. The first intron of the alpha 1(I) collagen gene contains several transcriptional regulatory elements. J Biol Chem. 1988 Feb 5;263(4):1603–1606. [PubMed] [Google Scholar]
  4. Breindl M., Harbers K., Jaenisch R. Retrovirus-induced lethal mutation in collagen I gene of mice is associated with an altered chromatin structure. Cell. 1984 Aug;38(1):9–16. doi: 10.1016/0092-8674(84)90521-x. [DOI] [PubMed] [Google Scholar]
  5. Chan H., Hartung S., Breindl M. Retrovirus-induced interference with collagen I gene expression in Mov13 fibroblasts is maintained in the absence of DNA methylation. Mol Cell Biol. 1991 Jan;11(1):47–54. doi: 10.1128/mcb.11.1.47. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Copeland N. G., Hutchison K. W., Jenkins N. A. Excision of the DBA ecotropic provirus in dilute coat-color revertants of mice occurs by homologous recombination involving the viral LTRs. Cell. 1983 Jun;33(2):379–387. doi: 10.1016/0092-8674(83)90419-1. [DOI] [PubMed] [Google Scholar]
  7. Harbers K., Kuehn M., Delius H., Jaenisch R. Insertion of retrovirus into the first intron of alpha 1(I) collagen gene to embryonic lethal mutation in mice. Proc Natl Acad Sci U S A. 1984 Mar;81(5):1504–1508. doi: 10.1073/pnas.81.5.1504. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hartung S., Jaenisch R., Breindl M. Retrovirus insertion inactivates mouse alpha 1(I) collagen gene by blocking initiation of transcription. 1986 Mar 27-Apr 2Nature. 320(6060):365–367. doi: 10.1038/320365a0. [DOI] [PubMed] [Google Scholar]
  9. Jaenisch R., Harbers K., Schnieke A., Löhler J., Chumakov I., Jähner D., Grotkopp D., Hoffmann E. Germline integration of moloney murine leukemia virus at the Mov13 locus leads to recessive lethal mutation and early embryonic death. Cell. 1983 Jan;32(1):209–216. doi: 10.1016/0092-8674(83)90511-1. [DOI] [PubMed] [Google Scholar]
  10. Jaenisch R., Jähner D., Nobis P., Simon I., Löhler J., Harbers K., Grotkopp D. Chromosomal position and activation of retroviral genomes inserted into the germ line of mice. Cell. 1981 May;24(2):519–529. doi: 10.1016/0092-8674(81)90343-3. [DOI] [PubMed] [Google Scholar]
  11. Jenkins N. A., Copeland N. G., Taylor B. A., Lee B. K. Dilute (d) coat colour mutation of DBA/2J mice is associated with the site of integration of an ecotropic MuLV genome. Nature. 1981 Oct 1;293(5831):370–374. doi: 10.1038/293370a0. [DOI] [PubMed] [Google Scholar]
  12. Jähner D., Jaenisch R. Chromosomal position and specific demethylation in enhancer sequences of germ line-transmitted retroviral genomes during mouse development. Mol Cell Biol. 1985 Sep;5(9):2212–2220. doi: 10.1128/mcb.5.9.2212. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Jähner D., Jaenisch R. Integration of Moloney leukaemia virus into the germ line of mice: correlation between site of integration and virus activation. Nature. 1980 Oct 2;287(5781):456–458. doi: 10.1038/287456a0. [DOI] [PubMed] [Google Scholar]
  14. Jähner D., Jaenisch R. Retrovirus-induced de novo methylation of flanking host sequences correlates with gene inactivity. Nature. 1985 Jun 13;315(6020):594–597. doi: 10.1038/315594a0. [DOI] [PubMed] [Google Scholar]
  15. Jähner D., Stuhlmann H., Stewart C. L., Harbers K., Löhler J., Simon I., Jaenisch R. De novo methylation and expression of retroviral genomes during mouse embryogenesis. Nature. 1982 Aug 12;298(5875):623–628. doi: 10.1038/298623a0. [DOI] [PubMed] [Google Scholar]
  16. Kratochwil K., von der Mark K., Kollar E. J., Jaenisch R., Mooslehner K., Schwarz M., Haase K., Gmachl I., Harbers K. Retrovirus-induced insertional mutation in Mov13 mice affects collagen I expression in a tissue-specific manner. Cell. 1989 Jun 2;57(5):807–816. doi: 10.1016/0092-8674(89)90795-2. [DOI] [PubMed] [Google Scholar]
  17. Lemischka I., Sharp P. A. The sequences of an expressed rat alpha-tubulin gene and a pseudogene with an inserted repetitive element. Nature. 1982 Nov 25;300(5890):330–335. doi: 10.1038/300330a0. [DOI] [PubMed] [Google Scholar]
  18. Lenardo M. J., Baltimore D. NF-kappa B: a pleiotropic mediator of inducible and tissue-specific gene control. Cell. 1989 Jul 28;58(2):227–229. doi: 10.1016/0092-8674(89)90833-7. [DOI] [PubMed] [Google Scholar]
  19. Levis R., O'Hare K., Rubin G. M. Effects of transposable element insertions on RNA encoded by the white gene of Drosophila. Cell. 1984 Sep;38(2):471–481. doi: 10.1016/0092-8674(84)90502-6. [DOI] [PubMed] [Google Scholar]
  20. Liau G., Yamada Y., de Crombrugghe B. Coordinate regulation of the levels of type III and type I collagen mRNA in most but not all mouse fibroblasts. J Biol Chem. 1985 Jan 10;260(1):531–536. [PubMed] [Google Scholar]
  21. Liska D. J., Slack J. L., Bornstein P. A highly conserved intronic sequence is involved in transcriptional regulation of the alpha 1(I) collagen gene. Cell Regul. 1990 May;1(6):487–498. doi: 10.1091/mbc.1.6.487. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Loh T. P., Sievert L. L., Scott R. W. Proviral sequences that restrict retroviral expression in mouse embryonal carcinoma cells. Mol Cell Biol. 1987 Oct;7(10):3775–3784. doi: 10.1128/mcb.7.10.3775. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Löhler J., Timpl R., Jaenisch R. Embryonic lethal mutation in mouse collagen I gene causes rupture of blood vessels and is associated with erythropoietic and mesenchymal cell death. Cell. 1984 Sep;38(2):597–607. doi: 10.1016/0092-8674(84)90514-2. [DOI] [PubMed] [Google Scholar]
  24. Melton D. A., Krieg P. A., Rebagliati M. R., Maniatis T., Zinn K., Green M. R. Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter. Nucleic Acids Res. 1984 Sep 25;12(18):7035–7056. doi: 10.1093/nar/12.18.7035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Modolell J., Bender W., Meselson M. Drosophila melanogaster mutations suppressible by the suppressor of Hairy-wing are insertions of a 7.3-kilobase mobile element. Proc Natl Acad Sci U S A. 1983 Mar;80(6):1678–1682. doi: 10.1073/pnas.80.6.1678. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Niwa O., Yokota Y., Ishida H., Sugahara T. Independent mechanisms involved in suppression of the Moloney leukemia virus genome during differentiation of murine teratocarcinoma cells. Cell. 1983 Apr;32(4):1105–1113. doi: 10.1016/0092-8674(83)90294-5. [DOI] [PubMed] [Google Scholar]
  27. Parkhurst S. M., Corces V. G. Forked, gypsys, and suppressors in Drosophila. Cell. 1985 Jun;41(2):429–437. doi: 10.1016/s0092-8674(85)80016-7. [DOI] [PubMed] [Google Scholar]
  28. Paro R., Goldberg M. L., Gehring W. J. Molecular analysis of large transposable elements carrying the white locus of Drosophila melanogaster. EMBO J. 1983;2(6):853–860. doi: 10.1002/j.1460-2075.1983.tb01513.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Rippe R. A., Lorenzen S. I., Brenner D. A., Breindl M. Regulatory elements in the 5'-flanking region and the first intron contribute to transcriptional control of the mouse alpha 1 type I collagen gene. Mol Cell Biol. 1989 May;9(5):2224–2227. doi: 10.1128/mcb.9.5.2224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rossi P., de Crombrugghe B. Identification of a cell-specific transcriptional enhancer in the first intron of the mouse alpha 2 (type I) collagen gene. Proc Natl Acad Sci U S A. 1987 Aug;84(16):5590–5594. doi: 10.1073/pnas.84.16.5590. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Rossouw C. M., Vergeer W. P., du Plooy S. J., Bernard M. P., Ramirez F., de Wet W. J. DNA sequences in the first intron of the human pro-alpha 1(I) collagen gene enhance transcription. J Biol Chem. 1987 Nov 5;262(31):15151–15157. [PubMed] [Google Scholar]
  32. Schmidt A., Rossi P., de Crombrugghe B. Transcriptional control of the mouse alpha 2(I) collagen gene: functional deletion analysis of the promoter and evidence for cell-specific expression. Mol Cell Biol. 1986 Feb;6(2):347–354. doi: 10.1128/mcb.6.2.347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Schnieke A., Dziadek M., Bateman J., Mascara T., Harbers K., Gelinas R., Jaenisch R. Introduction of the human pro alpha 1(I) collagen gene into pro alpha 1(I)-deficient Mov-13 mouse cells leads to formation of functional mouse-human hybrid type I collagen. Proc Natl Acad Sci U S A. 1987 Feb;84(3):764–768. doi: 10.1073/pnas.84.3.764. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Schnieke A., Harbers K., Jaenisch R. Embryonic lethal mutation in mice induced by retrovirus insertion into the alpha 1(I) collagen gene. 1983 Jul 28-Aug 3Nature. 304(5924):315–320. doi: 10.1038/304315a0. [DOI] [PubMed] [Google Scholar]
  35. Seperack P. K., Strobel M. C., Corrow D. J., Jenkins N. A., Copeland N. G. Somatic and germ-line reverse mutation rates of the retrovirus-induced dilute coat-color mutation of DBA mice. Proc Natl Acad Sci U S A. 1988 Jan;85(1):189–192. doi: 10.1073/pnas.85.1.189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Shinnick T. M., Lerner R. A., Sutcliffe J. G. Nucleotide sequence of Moloney murine leukaemia virus. Nature. 1981 Oct 15;293(5833):543–548. doi: 10.1038/293543a0. [DOI] [PubMed] [Google Scholar]
  37. Simchen G., Winston F., Styles C. A., Fink G. R. Ty-mediated gene expression of the LYS2 and HIS4 genes of Saccharomyces cerevisiae is controlled by the same SPT genes. Proc Natl Acad Sci U S A. 1984 Apr;81(8):2431–2434. doi: 10.1073/pnas.81.8.2431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Soriano P., Gridley T., Jaenisch R. Retroviruses and insertional mutagenesis in mice: proviral integration at the Mov 34 locus leads to early embryonic death. Genes Dev. 1987 Jun;1(4):366–375. doi: 10.1101/gad.1.4.366. [DOI] [PubMed] [Google Scholar]
  39. Southern P. J., Berg P. Transformation of mammalian cells to antibiotic resistance with a bacterial gene under control of the SV40 early region promoter. J Mol Appl Genet. 1982;1(4):327–341. [PubMed] [Google Scholar]
  40. Spence S. E., Gilbert D. J., Swing D. A., Copeland N. G., Jenkins N. A. Spontaneous germ line virus infection and retroviral insertional mutagenesis in eighteen transgenic Srev lines of mice. Mol Cell Biol. 1989 Jan;9(1):177–184. doi: 10.1128/mcb.9.1.177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Stacey A., Bateman J., Choi T., Mascara T., Cole W., Jaenisch R. Perinatal lethal osteogenesis imperfecta in transgenic mice bearing an engineered mutant pro-alpha 1(I) collagen gene. Nature. 1988 Mar 10;332(6160):131–136. doi: 10.1038/332131a0. [DOI] [PubMed] [Google Scholar]
  42. Stewart C. L., Stuhlmann H., Jähner D., Jaenisch R. De novo methylation, expression, and infectivity of retroviral genomes introduced into embryonal carcinoma cells. Proc Natl Acad Sci U S A. 1982 Jul;79(13):4098–4102. doi: 10.1073/pnas.79.13.4098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Stoye J. P., Fenner S., Greenoak G. E., Moran C., Coffin J. M. Role of endogenous retroviruses as mutagens: the hairless mutation of mice. Cell. 1988 Jul 29;54(3):383–391. doi: 10.1016/0092-8674(88)90201-2. [DOI] [PubMed] [Google Scholar]
  44. Stuhlmann H., Jähner D., Jaenisch R. Infectivity and methylation of retroviral genomes is correlated with expression in the animal. Cell. 1981 Oct;26(2 Pt 2):221–232. doi: 10.1016/0092-8674(81)90305-6. [DOI] [PubMed] [Google Scholar]
  45. Weiher H., Noda T., Gray D. A., Sharpe A. H., Jaenisch R. Transgenic mouse model of kidney disease: insertional inactivation of ubiquitously expressed gene leads to nephrotic syndrome. Cell. 1990 Aug 10;62(3):425–434. doi: 10.1016/0092-8674(90)90008-3. [DOI] [PubMed] [Google Scholar]
  46. Winston F., Chaleff D. T., Valent B., Fink G. R. Mutations affecting Ty-mediated expression of the HIS4 gene of Saccharomyces cerevisiae. Genetics. 1984 Jun;107(2):179–197. doi: 10.1093/genetics/107.2.179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Wu H., Bateman J. F., Schnieke A., Sharpe A., Barker D., Mascara T., Eyre D., Bruns R., Krimpenfort P., Berns A. Human-mouse interspecies collagen I heterotrimer is functional during embryonic development of Mov13 mutant mouse embryos. Mol Cell Biol. 1990 Apr;10(4):1452–1460. doi: 10.1128/mcb.10.4.1452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Zachar Z., Davison D., Garza D., Bingham P. M. A detailed developmental and structural study of the transcriptional effects of insertion of the Copia transposon into the white locus of Drosophila melanogaster. Genetics. 1985 Nov;111(3):495–515. doi: 10.1093/genetics/111.3.495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. van der Eb A. J., Graham F. L. Assay of transforming activity of tumor virus DNA. Methods Enzymol. 1980;65(1):826–839. doi: 10.1016/s0076-6879(80)65077-0. [DOI] [PubMed] [Google Scholar]

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