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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Gutmann, D.H. & Collins, F.S. von Recklinghausen neurofibromatosis. The Metabolic and Molecular Basis of Inherited Disease 1–19 (McGraw Hill, New York, 1994).
Huson, S.M. & Hughes, R.A.C. The Neurofibromatoses: A Pathogenic and Clinical Overview (Chapman & Hall, London, 1994).
Ozonoff, S. Cognitive impairment in neurofibromatosis type 1. Am. J. Med. Genet. 89, 45–52 (1999).
Ballester, R. et al. The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 63, 851–859 (1990).
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).
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).
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).
Jacks, T. et al. Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nature Genet. 7, 353–361 (1994).
Silva, A.J. et al. A mouse model for learning and memory deficits associated with neurofibromatosis type 1. Nature Genet. 15, 281–284 (1997).
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).
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).
Zeiher, B.G. et al. A mouse model for the delta F508 allele of cystic fibrosis. J. Clin. Invest. 96, 2051–2064 (1995).
Hogan, B., Beddington, R., Constantini, F. & Lacy, E. Manipulating the Mouse Embryo: A Laboratory Manual (Cold Spring Harbor Laboratory Press, New York, 1994).
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).
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).
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).
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).
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).
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).
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).
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).
Chen, C. et al. Impaired motor coordination correlates with persistent multiple climbing fiber innervation in PKCg mutant mice. Cell 83, 1233–1242 (1995).
Barlow, C. et al. Atm-deficient mice: a paradigm of ataxia telangietasia. Cell 86, 159–171 (1996).
Lijam, N. et al. Social interaction and sensimotor gating abnormalities in mice lacking Dvl1. Cell 90, 895–905 (1997).
Kogan, J.H. et al. Spaced training induces normal long-term memory in CREB mutant mice. Curr. Biol. 7, 1–11 (1997).
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).
Upadhyaya, M. & Cooper, D.N. (eds.) Neurofibromatosis Type 1: From Genotype to Phenotype (Bios Scientific Publisher, Oxford, 1998).
Gutmann, D.H., Zhang, Y. & Hirbe, A. Developmental regulation of a neuron-specific neurofibromatosis type 1 isoform. Ann. Neurol. 46, 777–782 (1999).
Klose, A. et al. Selective disactivation of neurofibromin GAP activity in neurofibromatosis type 1. Hum. Mol. Genet. 7, 1261–1268 (1998).
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).
Brambrilla, R. et al. A role for the Ras signalling pathway in synaptic transmission and long term memory. Nature 390, 281–286 (1997).
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).
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).
Metheny, L.J. & Skuse, G.R. NF1 mRNA isoform expression in PC12 cells: modulation by extrinsic factors. Exp. Cell Res. 228, 44–49 (1996).
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).
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).
Laird, P.W. et al. Simplified mammalian DNA isolation procedure. Nucleic Acids Res. 19, 4293–4294 (1991).
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).
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.
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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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