Mouse and Other Rodent Models of C to U RNA Editing

  • Valerie Blanc
  • Nicholas O. DavidsonEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 718)


Substitutional RNA editing represents an important posttranscriptional enzymatic pathway for increasing genetic plasticity by permitting production of different translation products from a single genomically encoded template. One of the best-characterized examples in mammals is C to U deamination of the nuclear apolipoprotein B (apoB) mRNA. ApoB mRNA undergoes a single, site-specific cytidine deamination event yielding an edited transcript that results in tissue-specific translation of two distinct isoforms, referred to as apoB100 and apoB48. Tissue- and site-specific cytidine deamination of apoB mRNA is mediated by an incompletely characterized holoenzyme containing a minimal core complex consisting of an RNA-specific cytidine deaminase, Apobec-1 and a requisite cofactor, apobec-1 complementation factor (ACF). The underlying biochemical and genetic mechanisms regulating tissue-specific apoB mRNA editing have been accelerated through development and characterization of physiological rodent models as well as knockout and transgenic animal strains.

Key words

Lipid metabolism RNA editing Apobec-1 Hepatocytes Hormonal regulation Diet Primer extension Subcellular distribution 



Work cited in this review was supported by grants from the National Institutes of Health (HL-38180, DK-56260, DK-52574) to NOD. The authors are deeply grateful to Susan Kennedy and Jianyang Luo for assistance with the murine models quoted in this review.


  1. 1.
    Blanc, V., and Davidson, N. O. (2003) C-to-U RNA editing: mechanisms leading to genetic diversity. J Biol Chem 278, 1395–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Greeve, J., Altkemper, I., Dieterich, J. H., Greten, H., and Windler, E. (1993) Apolipoprotein B mRNA editing in 12 different mammalian species: hepatic expression is reflected in low concentrations of apoB-­containing plasma lipoproteins. J Lipid Res 34, 1367–83.PubMedGoogle Scholar
  3. 3.
    Giannoni, F., Bonen, D. K., Funahashi, T., Hadjiagapiou, C., Burant, C. F., and Davidson, N. O. (1994) Complementation of apolipoprotein B mRNA editing by human liver accompanied by secretion of apolipoprotein B48. J Biol Chem 269, 5932–6.PubMedGoogle Scholar
  4. 4.
    Davidson, N. O., and Shelness, G. S. (2000) Apolipoprotein B:mRNA editing, lipoprotein assembly and presecretory degradation. Annu Rev Nutr 20, 169–93.PubMedCrossRefGoogle Scholar
  5. 5.
    Teng, B., Burant, C. F., and Davidson, N. O. (1993) Molecular cloning of an apolipoprotein B messenger RNA editing protein. Science 260, 1816–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Mehta, A., Kinter, M. T., Sherman, N. E., and Driscoll, D. M. (2000) Molecular cloning of apobec-1 complementation factor, a novel RNA-binding protein involved in the editing of apolipoprotein B mRNA. Mol Cell Biol 20, 1846–54.PubMedCrossRefGoogle Scholar
  7. 7.
    Lellek, H., Kirsten, R., Diehl, I., Apostel, F., Buck, F., and Greeve, J. (2000) Purification and molecular cloning of a novel essential component of the apolipoprotein B mRNA editing enzyme-complex. J Biol Chem 275, 19848–56.PubMedCrossRefGoogle Scholar
  8. 8.
    Blanc, V., Henderson, J. O., Newberry, E. P., Kennedy, S., Luo, J., and Davidson, N. O. (2005) Targeted deletion of the murine apobec-1 complementation factor (acf) gene results in embryonic lethality. Mol Cell Biol 25, 7260–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Teng, B., Black, D. D., and Davidson, N. O. (1990) Apolipoprotein B messenger RNA editing is developmentally regulated in pig small intestine: nucleotide comparison of apolipoprotein B editing regions in five species. Biochem Biophys Res Commun 173, 74–80.PubMedCrossRefGoogle Scholar
  10. 10.
    Henderson, J. O., Blanc, V., and Davidson, N. O. (2001) Isolation, characterization and developmental regulation of the human apobec-1 complementation factor (ACF) gene. Biochim Biophys Acta 1522, 22–30.PubMedGoogle Scholar
  11. 11.
    Mansouri, A., Chowdhury, K., and Gruss, P. (1998) Follicular cells of the thyroid gland require Pax8 gene function. Nat Genet 19, 87–90.PubMedCrossRefGoogle Scholar
  12. 12.
    Flamant, F., Poguet, A. L., Plateroti, M., Chassande, O., Gauthier, K., Streichenberger, N., Mansouri, A., and Samarut, J. (2002) Congenital hypothyroid Pax8(−/−) mutant mice can be rescued by inactivating the TRalpha gene. Mol Endocrinol 16, 24–32.PubMedCrossRefGoogle Scholar
  13. 13.
    Mukhopadhyay, D., Plateroti, M., Anant, S., Nassir, F., Samarut, J., and Davidson, N. O. (2003) Thyroid hormone regulates hepatic triglyceride mobilization and apolipoprotein B messenger ribonucleic acid editing in a murine model of congenital hypothyroidism. Endocrinology 144, 711–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Philips, M. S., Liu, Q., Hammond, H. A., Dugan, V., Hey, P. J., Caskey, C. T., and Hess, J. F. (1996) Leptin receptor missense in the fatty Zucker rat. Nature Genet 13, 18–19.CrossRefGoogle Scholar
  15. 15.
    von Wronski, M. A., Hirano, K. I., Cagen, L. M., Wilcox, H. G., Raghow, R., Thorngate, F. E., Heimberg, M., Davidson, N. O., and Elam, M. B. (1998) Insulin increases expression of apobec-1, the catalytic subunit of the apolipoprotein B mRNA editing complex in rat hepatocytes. Metabolism 47, 869–73.CrossRefGoogle Scholar
  16. 16.
    Elam, M. B., von Wronski, M. A., Cagen, L., Thorngate, F., Kumar, P., Heimberg, M., and Wilcox, H. G. (1999) Apolipoprotein B mRNA editing and apolipoprotein gene expression in the liver of hyperinsulinemic fatty Zucker rats: relationship to very low density lipoprotein composition. Lipids 34, 809–16.PubMedCrossRefGoogle Scholar
  17. 17.
    Sowden, M. P., Ballatori, N., Jensen, K. L., Reed, L. H., and Smith, H. C. (2002) The editosome for cytidine to uridine mRNA editing has a native complexity of 27S: identification of intracellular domains containing active and inactive editing factors. J Cell Sci 115, 1027–39.PubMedGoogle Scholar
  18. 18.
    Lehmann, D. M., Galloway, C. A., Sowden, M. P., and Smith, H. C. (2006) Metabolic regulation of apoB mRNA editing is associated with phosphorylation of APOBEC-1 complementation factor. Nucleic Acids Res 34, 3299–308.PubMedCrossRefGoogle Scholar
  19. 19.
    Wiegman, C. H., Bandsma, R. H., Ouwens, M., van der Sluijs, F. H., Havinga, R., Boer, T., Reijngoud, D. J., Romijn, J. A., and Kuipers, F. (2003) Hepatic VLDL production in ob/ob mice is not stimulated by massive de novolipogenesis but is less sensitive to the suppressive effects of insulin. Diabetes 52, 1081–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Lee, G. H., Proenca, R., Montez, J. M., Carroll, K. M., Darvishzadeh, J. G., Lee, J. I., and Friedman, J. M. (1996) Abnormal splicing of the leptin receptor in diabetic mice. Nature 379, 632–5.PubMedCrossRefGoogle Scholar
  21. 21.
    Leiter, E. H., Coleman, D. L., Eisenstein, A. B., and Strack, I. (1980) A new mutation (db3j) at the diabetes locus in strain 129/j mice. Physiological and histological characterization. Diabetologia 19, 58–65.PubMedCrossRefGoogle Scholar
  22. 22.
    Kobayashi, K., Forte, T. M., Taniguchi, S., Ishida, B. Y., Oka, K., and Chan, L. (2000) The db/db mouse, a model for diabetic dyslipidemia: molecular characterization and effects of Western diet feeding. Metabolism 49, 22–31.PubMedCrossRefGoogle Scholar
  23. 23.
    Hirano, K., Young, S. G., Farese, R. V., Jr., Ng, J., Sande, E., Warburton, C., Powell-Braxton, L. M., and Davidson, N. O. (1996) Targeted disruption of the mouse apobec-1 gene abolishes apolipoprotein B mRNA editing and eliminates apolipoprotein B48. J Biol Chem 271, 9887–90.PubMedCrossRefGoogle Scholar
  24. 24.
    Nakamuta, M., Chang, B. H., Zsigmond, E., Kobayashi, K., Lei, H., Ishida, B. Y., Oka, K., Li, E., and Chan, L. (1996) Complete phenotypic characterization of apobec-1 knockout mice with a wild-type genetic background and a human apolipoprotein B trasngenic background and restoration of apolipoprotein B mRNA editing by somatic gene transfer of Apobec-1. J Biol Chem 271, 25981–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Yamanaka, S., Balestra, M. E., Ferrell, L. D., Fan, J., Arnold, K. S., Taylor, S., Taylor, J. M., and Innerarity, T. L. (1995) Apolipoprotein B mRNA-editing protein induces hepatocellular carcinoma and dysplasia in transgenic animals. Proc Natl Acad Sci U S A 92, 8483–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Yamanaka, S., Poksay, K. S., Driscoll, D. M., and Innerarity, T. L. (1996) Hyperediting of multiple cytidines of apolipoprotein B mRNA by APOBEC-1 requires auxiliary protein(s) but not a mooring sequence motif. J Biol Chem 271, 11506–10.PubMedCrossRefGoogle Scholar
  27. 27.
    Kistner, A., Gossen, M., Zimmermann, F., Jerecic, J., Ullmer, C., Lubbert, H., and Bujard, H. (1996) Doxycycline-meidated quantitative and tissue-specific control of gene expression in transgenic mice. Proc Natl Acad Sci U S A 93, 10933–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Hersberger, M., Patarroyo-White, S., Qian, X., Arnold, K. S., Rohrer, L., Balestra, M. E., and Innerarity, T. L. (2003) Regulatable liver expression of the rabbit apolipoprotein B mRNA-editing catalytic polypeptide 1 (APOBEC-1) in mice lacking endogenous APOBEC-1 leads to aberrant hyperediting. Biochem J 369, 255–62.PubMedCrossRefGoogle Scholar
  29. 29.
    Davidson, N. O., Powell, L. M., Wallis, S. C., and Scott, J. (1988) Thyroid hormone modulates the introduction of a stop codon in rat liver apolipoprotein B messenger RNA. J Biol Chem 263, 13482–5.PubMedGoogle Scholar
  30. 30.
    Plateroti, M., Chassande, O., Fraichard, A., Gauthier, K., Freund, J. N., Samarut, J., and Kedinger, M. (1999) Involvement of T3Ralpha-and beta-receptor subtypes in mediation of T3 functions during postnatal murine intestinal development. Gastroenterology 116, 1367–78.PubMedCrossRefGoogle Scholar
  31. 31.
    Srivastava, R. A. (1995) Increased apoB100 mRNA in inbred strains of mice by estrogen is caused by decreased RNA editing protein mRNA. Biochem Biophys Res Commun 212, 381–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Lau, P. P., Cahill, D. J., Zhu, H. J., and Chan, L. (1995) Ethanol modulates apolipoprotein B mRNA editing in the rat. J Lipid Res 36, 2069–78.PubMedGoogle Scholar
  33. 33.
    Baum, C. L., Teng, B. B., and Davidson, N. O. (1990) Apolipoprotein B messenger RNA editing in the rat liver. Modulation by fasting and refeeding a high carbohydrate diet. J Biol Chem 265, 19263–70.PubMedGoogle Scholar
  34. 34.
    MacGinnitie, A. J., Anant, S., and Davidson, N. O. (1995) Mutagenesis of apobec-1, the catalytic subunit of the mammalian apolipoprotein B mRNA editing enzyme reveals distinct domains that mediate cytosine nucleoside deaminase, RNA binding and RNA editing activity. J Biol Chem 270, 14768–75.PubMedCrossRefGoogle Scholar
  35. 35.
    Funahashi, T., Giannoni, F., DePaoli, A. M., Skarosi, S. F., and Davidson, N. O. (1995) Tissue-specific, developmental and nutritional regulation of the gene encoding the catalytic subunit of the rat apolipoprotein B mRNA editing enzyme: functional role in the modulation of apoB mRNA editing. J Lipid Res 36, 414–28.PubMedGoogle Scholar
  36. 36.
    Blanc, V., Henderson, J. O., Kennedy, S., and Davidson, N. O. (2001) Mutagenesis of apobec-1 complementation factor reveals distinct domains that modulate RNA binding, protein-protein interaction with apobec-1 and complementation of C to U RNA editing activity. J Biol Chem 276, 46386–93.PubMedCrossRefGoogle Scholar
  37. 37.
    Bonen, D. K., Nassir, F., Hausman, A. M., and Davidson, N. O. (1998) Inhibition of N-linked glycosylation results in retention of intracellular apo(a) in hepatoma cells, although nonglycosylated and immature forms of apolipoprotein(a) are competent to associate with apolipoprotein B-100 in vitro. J Lipid Res 39, 1629–40.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of MedicineWashington University School of MedicineSt. LouisUSA

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