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Learning deficits, but normal development and tumor predisposition, in mice lacking exon 23a of Nf1

Nature Genetics volume 27, pages 399–405 (2001)Cite this article

Abstract

Neurofibromatosis type 1 (NF1) is a commonly inherited autosomal dominant disorder. Previous studies indicated that mice homozygous for a null mutation in Nf1 exhibit mid-gestation lethality, whereas heterozygous mice have an increased predisposition to tumors and learning impairments. Here we show that mice lacking the alternatively spliced exon 23a, which modifies the GTPase-activating protein (GAP) domain of Nf1, are viable and physically normal, and do not have an increased tumor predisposition, but show specific learning impairments. Our findings have implications for the development of a treatment for the learning disabilities associated with NF1 and indicate that the GAP domain of NF1 modulates learning and memory.

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Figure 1: Strategy and analysis of targeted disruptions of Nf1 exon 23a.
Figure 2: Spatial learning in the water maze.
Figure 3: Contextual discrimination.
Figure 4: Motor performance in the rota-rod.
Figure 5: Social transmission of food preferences.

References

  1. Gutmann, D.H. & Collins, F.S. von Recklinghausen neurofibromatosis. The Metabolic and Molecular Basis of Inherited Disease 1–19 (McGraw Hill, New York, 1994).

  2. Huson, S.M. & Hughes, R.A.C. The Neurofibromatoses: A Pathogenic and Clinical Overview (Chapman & Hall, London, 1994).

    Google Scholar 

  3. Ozonoff, S. Cognitive impairment in neurofibromatosis type 1. Am. J. Med. Genet. 89, 45–52 (1999).

    Article  CAS  Google Scholar 

  4. 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  Google Scholar 

  5. 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  Google Scholar 

  6. Xu, G.F. 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  Google Scholar 

  7. 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 Dev. 8, 1019–1029 (1994).

    Article  CAS  Google Scholar 

  8. Jacks, T. et al. Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nature Genet. 7, 353–361 (1994).

    Article  CAS  Google Scholar 

  9. Silva, A.J. et al. A mouse model for learning and memory deficits associated with neurofibromatosis type 1. Nature Genet. 15, 281–284 (1997).

    Article  CAS  Google Scholar 

  10. Andersen, L.B. et al. A conserved alternative splice in the von Recklinghausen neurofibromatosis (NF1) gene produces two neurofibromin isoforms, both of which have GTPase-activating protein activity. Mol. Cell. Biol. 13, 478–495 (1993).

    Article  Google Scholar 

  11. Viskochil, D.H. Gene structure and function. in Neurofibromatosis Type 1: From Genotype to Phenotype (eds. Upadhyaya, M. & Cooper, D.N.) 39–56 (Bios Scientific Publishers, Oxford, 1998).

    Google Scholar 

  12. Zeiher, B.G. et al. A mouse model for the delta F508 allele of cystic fibrosis. J. Clin. Invest. 96, 2051–2064 (1995).

    Article  CAS  Google Scholar 

  13. Hogan, B., Beddington, R., Constantini, F. & Lacy, E. Manipulating the Mouse Embryo: A Laboratory Manual (Cold Spring Harbor Laboratory Press, New York, 1994).

    Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Gutmann, D.H., Cole, J.L. & Collins, F.S. Expression of the neurofibromatosis type 1 (NF1) gene during mouse embryonic development. Prog. Brain Res. 105, 327–335 (1995).

    Article  CAS  Google Scholar 

  16. Nordlund, M.L., Rizvi, T.A., Brannan, C.I. & Ratner, N. Neurofibromin expression and astrogliosis in neurofibromatosis (type I) brains. J. Neuropath. Exp. Neurol. 54, 588–600 (1995).

    Article  CAS  Google Scholar 

  17. Rizvi, T.A. et al. Region-specific astrogliosis in brains of mice heterozygous for mutations in the neurofibromatosis type I (Nf1) tumor suppressor. Brain Res. 816, 111–123 (1999).

    Article  CAS  Google Scholar 

  18. Cho, Y. & Silva, A.J. Ibotenate lesions of the hippocampus impair spatial learning but not contextual fear conditioning in mice. Behav. Brain Res. 98, 77–87 (1999).

    Article  CAS  Google Scholar 

  19. Brandeis, R., Brandys, Y. & Yehuda, S. The use of the Morris water maze in the study of memory and learning. Int. J. Neurosci. 48, 29–69 (1989).

    Article  CAS  Google Scholar 

  20. Gallagher, M., Burwell, R. & Burchinal, M. Severity of spatial impairments in aging: development of a spatial index for performance in the Morris water maze. Behav. Neurosci. 107, 618–626 (1993).

    Article  CAS  Google Scholar 

  21. Frankland, P.W., Cestari, V., Filipkowski, R.K., McDonald, R.J. & Silva, A.J. The dorsal hippocampus is essential for context discrimination but not for contextual conditioning. Behav. Neurosci. 112, 863–874 (1998).

    Article  CAS  Google Scholar 

  22. Chen, C. et al. Impaired motor coordination correlates with persistent multiple climbing fiber innervation in PKCg mutant mice. Cell 83, 1233–1242 (1995).

    Article  CAS  Google Scholar 

  23. Barlow, C. et al. Atm-deficient mice: a paradigm of ataxia telangietasia. Cell 86, 159–171 (1996).

    Article  CAS  Google Scholar 

  24. Lijam, N. et al. Social interaction and sensimotor gating abnormalities in mice lacking Dvl1. Cell 90, 895–905 (1997).

    Article  CAS  Google Scholar 

  25. Kogan, J.H. et al. Spaced training induces normal long-term memory in CREB mutant mice. Curr. Biol. 7, 1–11 (1997).

    Article  CAS  Google Scholar 

  26. Bunsey, M. & Eichenbaum, H. Selective damage to the hippocampal region blocks long-term retention of a natural and non-spatial stimulus-stimulus association. Hippocampus 5, 546–556 (1995).

    Article  CAS  Google Scholar 

  27. Upadhyaya, M. & Cooper, D.N. (eds.) Neurofibromatosis Type 1: From Genotype to Phenotype (Bios Scientific Publisher, Oxford, 1998).

    Google Scholar 

  28. Gutmann, D.H., Zhang, Y. & Hirbe, A. Developmental regulation of a neuron-specific neurofibromatosis type 1 isoform. Ann. Neurol. 46, 777–782 (1999).

    Article  CAS  Google Scholar 

  29. Klose, A. et al. Selective disactivation of neurofibromin GAP activity in neurofibromatosis type 1. Hum. Mol. Genet. 7, 1261–1268 (1998).

    Article  CAS  Google Scholar 

  30. Atkins, C.M., Selcher, J.C., Petraitis, J.J., Trzaskos, J.M. & Sweatt, J.D. The MAPK cascade is required for mammalian associative learning. Nature Neurosci. 1, 602–609 (1998).

    Article  CAS  Google Scholar 

  31. Brambrilla, R. et al. A role for the Ras signalling pathway in synaptic transmission and long term memory. Nature 390, 281–286 (1997).

    Article  Google Scholar 

  32. Largaespada, D.L., Brannan, C.I., Jenkins, N.A. & Copeland, N.G. Nf1 deficiency causes Ras-mediated granulocyte/macrophage stimulating factor hypersensitivity and chronic myeloid leukemia. Nature Genet. 12, 137–143 (1996).

    Article  CAS  Google Scholar 

  33. Bollag, G. et al. Loss of Nf1 results in activation of the Ras signalling pathway and leads to aberrant growth in hematopoietic cells. Nature Genet. 12, 144–148 (1996).

    Article  CAS  Google Scholar 

  34. Metheny, L.J. & Skuse, G.R. NF1 mRNA isoform expression in PC12 cells: modulation by extrinsic factors. Exp. Cell Res. 228, 44–49 (1996).

    Article  CAS  Google Scholar 

  35. Swiatek, P.J. & Gridley, T. Perinatal lethality and defects in hindbrain development in mice homozygous for a targeted mutation of the zinc finger gene Krox20. Genes Dev. 7, 2071–2084 (1993).

    Article  CAS  Google Scholar 

  36. Robertson, E.J. Embryo-derived stem cells. in Teratocarcinomas and Embryonic Stem Cells: A Practical Approach (ed. Robertson, E.J.) 71–112 (IRL, Oxford, 1987).

    Google Scholar 

  37. Laird, P.W. et al. Simplified mammalian DNA isolation procedure. Nucleic Acids Res. 19, 4293–4294 (1991).

    Article  CAS  Google Scholar 

  38. Bourtchuladze, R. et al. Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell 79, 59–68 (1994).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank K. Thomas for the KT3NP4 neomycin cassette; R. White for support in the generation of the GAP4 antibody; D.H. Gutmann for help interpreting the immunohistochemistry; P.W. Frankland for discussions; and C.M. Spivak for inspiration and support. R.C.M. is supported by the GABBA Graduate Program (Oporto University) and the Portuguese Foundation for Science and Technology (BD 13854/97). This work was supported by a grant from the Department of Defense, U.S. Army Medical Research and Materiel Command (DAMD17-97-1-7339) to C.I.B.; grants from the NIH (R01 NS38480), the Neurofibromatosis Consortium and the Neurofibromatosis Foundation to A.J.S.; and a donation from C.M. Spivak to A.J.S.

Author information

Author notes

  1. Tao Yang

    Present address: Brigham and Woman's Hospital, Boston, Massachusetts, USA

  2. Rui M. Costa and Tao Yang: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Neurobiology, Psychiatry and Psychology, BRI, UCLA, Los Angeles, California, USA

    Rui M. Costa & Alcino J. Silva

  2. Department of Molecular Genetics and Microbiology, Center for Mammalian Genetics, and the University of Florida Brain Institute, University of Florida College of Medicine, Gainesville, Florida, USA

    Tao Yang & Camilynn I. Brannan

  3. Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, California, USA

    Duong P. Huynh & Stefan M. Pulst

  4. Division of Medical Genetics, University of Utah, Salt Lake City, Utah, USA

    David H. Viskochil

Authors
  1. Rui M. Costa
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  2. Tao Yang
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Correspondence to Alcino J. Silva or Camilynn I. Brannan.

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Costa, R., Yang, T., Huynh, D. et al. Learning deficits, but normal development and tumor predisposition, in mice lacking exon 23a of Nf1. Nat Genet 27, 399–405 (2001). https://doi.org/10.1038/86898

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