Abstract
Neurofibromatosis type 1 (NF1) is a prevalent genetic disorder that affects growth properties of neural-crest-derived cell populations. In addition, approximately one-half of NF1 patients exhibit learning disabilities. To characterize NF1 function both in vitro and in vivo, we circumvent the embryonic lethality of NF1 null mouse embryos by generating a conditional mutation in the NF1 gene using Cre/loxP technology. Introduction of a Synapsin I promoter driven Cre transgenic mouse strain into the conditional NF1 background has ablated NF1 function in most differentiated neuronal populations. These mice have abnormal development of the cerebral cortex, which suggests that NF1 has an indispensable role in this aspect of CNS development. Furthermore, although they are tumor free, these mice display extensive astrogliosis in the absence of conspicuous neurodegeneration or microgliosis. These results indicate that NF1-deficient neurons are capable of inducing reactive astrogliosis via a non-cell autonomous mechanism.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alleles
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Animals
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Cell Transformation, Neoplastic / genetics
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Cells, Cultured
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Cerebral Cortex / abnormalities*
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Cerebral Cortex / embryology
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Disease Models, Animal*
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Ganglia, Spinal / pathology
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Gene Expression Regulation, Developmental
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Genes, Neurofibromatosis 1
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Genes, Reporter
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Genes, Synthetic
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Genetic Vectors / genetics
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Gliosis / metabolism*
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Integrases / genetics
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Integrases / physiology
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Lac Operon
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Learning Disabilities / genetics
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MAP Kinase Signaling System / genetics
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Mice
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Mice, Knockout
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Mice, Neurologic Mutants
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Mice, Transgenic
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Nerve Tissue Proteins / deficiency
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / physiology*
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Neurofibromin 1
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Neurons / metabolism
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Promoter Regions, Genetic
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Proto-Oncogene Proteins p21(ras) / physiology
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Recombinant Fusion Proteins / biosynthesis
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / physiology
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Signal Transduction
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Synapsins / genetics
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Viral Proteins*
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p120 GTPase Activating Protein / genetics
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p120 GTPase Activating Protein / physiology
Substances
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Nerve Tissue Proteins
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Neurofibromin 1
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Recombinant Fusion Proteins
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Synapsins
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Viral Proteins
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p120 GTPase Activating Protein
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Cre recombinase
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Integrases
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Proto-Oncogene Proteins p21(ras)