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Tumour predisposition in mice heterozygous for a targeted mutation in Nf1

Abstract

Human neurofibromatosis type 1 is a dominant disease caused by the inheritance of a mutant allele of the NF1 gene. In order to study NF1 function, we have constructed a mouse strain carrying a germline mutation in the murine homologue. Heterozygous animals do not exhibit the classical symptoms of the human disease, but are highly predisposed to the formation of various tumour types, notably phaeochomocytoma, a tumour of the neural crest–derived adrenal medulla, and myeloid leukaemia, both of which occur with increased frequency in human NF1 patients. The wild–type Nf1 allele is lost in approximately half of the tumours from heterozygous animals. In addition, homozygosity for the Nf1 mutation leads to abnormal cardiac development and mid–gestational embryonic lethality.

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References

  1. Stumph, D.A. et al. Neurofibromatosis. Arch. Neurol. 45, 575–578 (1987).

    Google Scholar 

  2. Riccardi, V.M., M.D. Neurofibromatosis: Phenotype, Natural History, and Pathogenesis. (Johns Hopkins University, Baltimore, 1992).

    Google Scholar 

  3. Hope, D.G. & Mulvihill, J.J. Malignancy in neurofibromatosis. Adv. Neurol. 29, 33–55 (1981).

    CAS  PubMed  Google Scholar 

  4. Bolande, R.P. The neurocristopathies: a unifying concept of disease arising in neural crest maldevelopment. Hum. Pathol. 5, 409–429 (1974).

    Article  Google Scholar 

  5. Cawthon, R.M. et al. A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell 62, 193–201 (1990).

    Article  CAS  PubMed  Google Scholar 

  6. Viskoshil, D. et al. Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell 62, 187–192 (1990).

    Article  Google Scholar 

  7. Wallace, M.R. et al. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 249, 181–186 (1990).

    Article  CAS  PubMed  Google Scholar 

  8. Xu, G. et al. The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 62, 599–608 (1990).

    Article  CAS  PubMed  Google Scholar 

  9. Martin, G.A. et al. The GAP–related domain of the neurofibromatosis type 1 gene product Interacts with ras p21. Cell 63, 843–849 (1990).

    Article  CAS  PubMed  Google Scholar 

  10. Xu, G. et al. The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae. Cell 63, 835–841 (1990).

    Article  CAS  PubMed  Google Scholar 

  11. Ballester, R. et al. The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 63, 851–859 (1990).

    Article  CAS  PubMed  Google Scholar 

  12. DeClue, J.E., Cohen, B.D. & Lowy, D.R. Identification and characterization of the neurofibromatosis type 1 protein product. Proc. natn. Acad. Sci. U.S.A. 88, 9914–9918 (1991).

    Article  CAS  Google Scholar 

  13. Basu, T.N. et al. Aberrant regulation of ras proteins in malignant tumur cells from type 1 neurofibromatosis patients. Nature 356, 713–715 (1992).

    Article  CAS  PubMed  Google Scholar 

  14. Daston, M.M. & Ratner, N. Neurofibromin, a predominantly neuronal GTPase activating protein in the adult, is ubiquitiously expressed during development. Devel. Dynamics 195, 216–226 (1992).

    Article  CAS  Google Scholar 

  15. Huynh, D.P., Nechiporuk, T. & Pulst, S.M. Differential expression and tissue distribution of type I and type II Neurofibromins during mouse fetal development. Devel. Biol. 161, 538–551 (1994).

    Article  CAS  Google Scholar 

  16. Daston, M.M. et al. The protein product of the neurofibromatosis type 1 gene is expressed at highest abundance in neurons, schwann cells, and oligodendrocytes. Neuron 8, 415–428 (1992).

    Article  CAS  PubMed  Google Scholar 

  17. Seizinger, B.R. NF1 :aprevalent cause of tumourigenesisin human cancers? Nature Genet. 3, 97–99 (1993).

    Article  CAS  PubMed  Google Scholar 

  18. Knudson, J.A.G. Mutation and cancer statistical study of retinoblastoma. Proc. natn. Acad. Sci. U.S.A. 68, 820–823 (1971).

    Article  Google Scholar 

  19. Legius, E., Marchuk, D.A., Collins, F.S. & Glover, T.W. Somatic deletion of the neurofibromatosis type 1 gene in a neurofibrosarcoma supports a tumour suppressor gene hypothesis. Nature Genet. 3, 122–126 (1993).

    Article  CAS  PubMed  Google Scholar 

  20. DeClue, J.E. et al. Abnormal regulation of mammalian p21ras contributes to malignant tumor growth in von Recklinghausen (type 1) neurofibromatosis. Cell 69, 265–273 (1992).

    Article  CAS  PubMed  Google Scholar 

  21. Li, Y. et al. Somatic mutations in the neurofibromatosis 1 gene in human tumours. Cell 69, 275–281 (1992).

    Article  CAS  PubMed  Google Scholar 

  22. Andersen, L.B. et al. Mutations in the neurofibromatosis 1 gene in sporadic malignant melanoma cell lines. Nature Genet. 3, 118–121 (1993).

    Article  CAS  PubMed  Google Scholar 

  23. Johnson, M.R., Look, A.T., DeClue, J.E., Valentine, M.B. & Lowy, D.R. Inactivation of the NF1 gene in human melanoma and neuroblastoma cell lines without Impaired regulation of GTP ras. Proc. natn. Acad. Sci. U.S.A. 90, 5539–5543 (1993).

    Article  CAS  Google Scholar 

  24. The, I. et al. Neurofibromatosis type 1 gene mutations in neuroblatoma. Nature Genet. 3, 62–66 (1993).

    Article  CAS  PubMed  Google Scholar 

  25. Bernards, A., Snijders, A.J., Hannigan, G.E., Murthy, A.E. & Gusella, J.F. Mouse neurofibromatosis type 1 cDNA sequence reveals high degree of conservation of both coding and non-coding mRNA segments. Hum. molec. Genet. 2, 645–650 (1993).

    Article  CAS  PubMed  Google Scholar 

  26. Brannan, C.I. et al. Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues. Genes Devel. 8, 1019–1029 (1994).

    Article  CAS  PubMed  Google Scholar 

  27. Estivill, X., Lazaro, C., Casals, T. & Ravella, A. Recurrence of a nonsense mutation In the NF1 gene causing classical neurofibromatosis type 1. Hum. Genet. 88, 185–188 (1991).

    Article  CAS  PubMed  Google Scholar 

  28. Ainsworth, P.J., Rodenhiser, D.I. & Costa, M.T. Identification and characterization of sporadic and Inherited mutations In exon 31 of the neurofibromatosis (NF1) gene. Hum. Genet. 91, 151–156 (1993).

    Article  CAS  PubMed  Google Scholar 

  29. Mansour, S.L., Thomas, K.R. & Capecchi, M.R. Disruption of the protoonco gene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genes. Nature 336, 348–352 (1988).

    Article  CAS  PubMed  Google Scholar 

  30. Gossler, A., Doetschman, T., Korn, R., Serfling, E. & Kemier, R. Transgenesis by means of blastocyst-derived embryonic stem cell lines. Proc. natn. Acad. Sci. U.S.A. 83, 9065–9069 (1986).

    Article  CAS  Google Scholar 

  31. Bronson, R.T. Rate of occurrence of lesions in 20 inbred and hybrid genotypes of rats and mice sacrificed at 6 month intervals during the first years of life. In Genetics of Aging II, (ed. Harrison, D.E.) 280–358 (Telford, New Jersey, 1990).

    Google Scholar 

  32. Riccardi, V.M. von Recklinghausen neurofibromatosis. New Engl. J. Med. 305, 1617–1627 (1981).

    Article  CAS  PubMed  Google Scholar 

  33. Chetty, R. & Duhig, J.D. Bilateral pheochromocytoma-ganglioneuroma of the adrenal In type 1 neuroflbromatosis. Am. J. surg. Pathol. 17, 837–841 (1993).

    Article  CAS  PubMed  Google Scholar 

  34. Le Douarin, N.M. The Neural Crest. (Cambridge University, Cambridge, 1982).

    Google Scholar 

  35. Shannon, K.M., Loss of the normal NF1 allele from the bone marrow of children with type 1 neurofibromatosis and malignant myeloid disorders. New Engl. J. Med. 330, 597–601 (1994).

    Article  CAS  PubMed  Google Scholar 

  36. Kirby, M.L., Gale, T.F. & Stewart, D.E. Neural crest cells contribute to aorticopulmonary septation. Science 220, 1059–1061 (1983).

    Article  CAS  PubMed  Google Scholar 

  37. Xu, W. et al. Loss of NF1 alleles in pheochromocytoma from patients with type I neurofibromatosis. Genes Chrom. Cancer 4, 337–342 (1992).

    Article  CAS  PubMed  Google Scholar 

  38. Jacks, T. et al. Effects of an Rb mutation in the mouse. Nature 359, 295–300 (1992).

    Article  CAS  PubMed  Google Scholar 

  39. Lee, E.Y.Y.-H.P. et al. Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 359, 288–295 (1992).

    Article  CAS  PubMed  Google Scholar 

  40. Clarke, A.R. et al. Requirement for a functional Rb-1 gene in murine development. Nature 359, 328–330 (1992).

    Article  CAS  PubMed  Google Scholar 

  41. Hooper, M., Hardy, K., Handyside, A., Hunter, S. & Monk, M. HPRT-deflcient (Leech-Nyhan)mouse embryos derived from germline colonization by cultured cells. Nature 326, 292–295 (1987).

    Article  CAS  PubMed  Google Scholar 

  42. Keuhn, M.R., Bradley, M., Robertson, E.J. & Evans, M.J. A potential animal model for Lesoh-Nyhan Syndrome through introduction of HPRT mutations into mice. Nature 326, 295–298 (1987).

    Article  Google Scholar 

  43. Easton, D.F., Ponder, M.A., Huson, S.M. & Ponder, B.A.J. An analysis of variation in expression of neurofibromatosis (NF) type 1 (NF1): evidence for modifying genes. Am. J. hum. Genet. 53, 305–313 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Hinrichs, S.H., Nerenberg, M., Reynolds, R.K., Khoury, G. & Jay, G. A transgenic mouse model for human neurofibromatosis. Science 237, 1340–1343 (1987).

    Article  CAS  PubMed  Google Scholar 

  45. Green, J.E., Baird, A.M., Hinrichs, S.H., Klintworth, G.K. & Jay, G. Adrenal medullary tumors and Iris proliferation in a transgenic mouse model of neuroflbromatosis. Am. J. pathol. 140, 1401–1410 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Kirby, M.L. & Waldo, K.L. Role of neural crest In congenital heart disease. Circulation 82, 332–340 (1990).

    Article  CAS  PubMed  Google Scholar 

  47. Epstein, D.J., Vekemans, M. & Gros, P. splotch (Sp2H), a mutation affecting development of the mouse neural tube, shows a deletion within the paired homeodomain of Pax-3. Cell 67, 767–774 (1991).

    Article  CAS  PubMed  Google Scholar 

  48. Franz, T. Persistent truncus arteriosus in the Splotch mutant mouse. Anat. Embryol. 180, 457–464 (1989).

    Article  CAS  Google Scholar 

  49. Gutmann, D.H., Andersen, L.B., Cole, J.L., Swaroop, M. & Collins, F.S. An alternatively-spliced mRNA in the carboxy terminus of the neurofibromatosis type 1 (NF1) gene is expressed in muscle. Hum. molec. Genet. 2, 989–992 (1993).

    Article  CAS  Google Scholar 

  50. Tassabehji, M. et al. Tandem duplication within a Neuroflbromatosis type I (NF1) gene exon in a family with features of Watson Syndrome and Noonan Syndrome. Am. J. hum. Genet. 53, 90–95 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Thomas, K.R. & Capecchi, M.R. Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells. Cell 51, 503–512 (1987).

    Article  CAS  PubMed  Google Scholar 

  52. Shackleford, G.M. & Varmus, H.E. Expression of the proto-oncogene int-1 is restricted to postmeiotic male germ cells and the neural tube of mid-gestational embryos. Cell 50, 89–95 (1987).

    Article  CAS  PubMed  Google Scholar 

  53. Robertson, E.J. Embryo-derived stem cell lines. In Teratocarcinomas and embryonic stem cells: a practical approach, (ed. Roberton, E.J.) 77–78 (IRL, Oxford, 1987).

    Google Scholar 

  54. Xie, W.-Q. & Rothblum, L.I. Rapid, small-scale RNA isolation from tissue culture cells. BioTechniques 11, 325–327 (1991).

    Google Scholar 

  55. Ausubel, F.M. et al. Current Protocols in Molecular Biology (Wiley, Boston, 1994).

    Google Scholar 

  56. Laird, P.W. et al. Simplified mammalian DNA Isolation procedure. Nucl. Acids Res. 19, 4293 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Jacks, T., Shih, T., Schmitt, E. et al. Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nat Genet 7, 353–361 (1994). https://doi.org/10.1038/ng0794-353

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