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      A porcine model of neurofibromatosis type 1 that mimics the human disease

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          Abstract

          <p class="first" id="d8411972e469">Loss of the <i>NF1</i> tumor suppressor gene causes the autosomal dominant condition, neurofibromatosis type 1 (NF1). Children and adults with NF1 suffer from pathologies including benign and malignant tumors to cognitive deficits, seizures, growth abnormalities, and peripheral neuropathies. <i>NF1</i> encodes neurofibromin, a Ras-GTPase activating protein, and <i>NF1</i> mutations result in hyperactivated Ras signaling in patients. Existing <i>NF1</i> mutant mice mimic individual aspects of NF1, but none comprehensively models the disease. We describe a potentially novel Yucatan miniswine model bearing a heterozygotic mutation in <i>NF1</i> (exon 42 deletion) orthologous to a mutation found in NF1 patients. <i>NF1 <sup>+/ex42del</sup> </i> miniswine phenocopy the wide range of manifestations seen in NF1 patients, including café au lait spots, neurofibromas, axillary freckling, and neurological defects in learning and memory. Molecular analyses verified reduced neurofibromin expression in swine <i>NF1 <sup>+/ex42del</sup> </i> fibroblasts, as well as hyperactivation of Ras, as measured by increased expression of its downstream effectors, phosphorylated ERK1/2, SIAH, and the checkpoint regulators p53 and p21. Consistent with altered pain signaling in NF1, dysregulation of calcium and sodium channels was observed in dorsal root ganglia expressing mutant <i>NF1</i>. Thus, these <i>NF1 <sup>+/ex42del</sup> </i> miniswine recapitulate the disease and provide a unique, much-needed tool to advance the study and treatment of NF1. </p><p class="first" id="d8411972e509">A miniswine model bearing a heterozygotic mutation in NF1, orthologous to a mutation in NF1 patients, phenocopies a range of manifestations seen in diseased patients. </p>

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          Most cited references63

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          Ablation of NF1 function in neurons induces abnormal development of cerebral cortex and reactive gliosis in the brain.

          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.
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            Neurofibromin regulation of ERK signaling modulates GABA release and learning.

            We uncovered a role for ERK signaling in GABA release, long-term potentiation (LTP), and learning, and show that disruption of this mechanism accounts for the learning deficits in a mouse model for learning disabilities in neurofibromatosis type I (NF1). Our results demonstrate that neurofibromin modulates ERK/synapsin I-dependent GABA release, which in turn modulates hippocampal LTP and learning. An Nf1 heterozygous null mutation, which results in enhanced ERK and synapsin I phosphorylation, increased GABA release in the hippocampus, and this was reversed by pharmacological downregulation of ERK signaling. Importantly, the learning deficits associated with the Nf1 mutation were rescued by a subthreshold dose of a GABA(A) antagonist. Accordingly, Cre deletions of Nf1 showed that only those deletions involving inhibitory neurons caused hippocampal inhibition, LTP, and learning abnormalities. Importantly, our results also revealed lasting increases in GABA release triggered by learning, indicating that the mechanisms uncovered here are of general importance for learning.
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              Epidemiology of neurofibromatosis type 1.

              The prevalence of neurofibromatosis type 1 (NF1) is about 1/3,000. There are no known ethnic groups in which NF1 does not occur or is unusually common. The prevalence is somewhat higher in young children than in adults, a difference that probably results at least in part from the early death of some NF1 patients. NF1 is fully penetrant in adults, but many disease features increase in frequency or severity with age. The reproductive fitness of NF1 patients is reduced by about one-half. About half of all cases result from new mutations. The estimated rate of new NF1 mutations is unusually high, but the basis for this high mutation rate is not known. Am. J. Med. Genet. (Semin. Med. Genet.) 89:1-6, 1999. Copyright 1999 Wiley-Liss, Inc.
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                Author and article information

                Journal
                JCI Insight
                American Society for Clinical Investigation
                2379-3708
                June 21 2018
                June 21 2018
                June 21 2018
                June 21 2018
                : 3
                : 12
                Article
                10.1172/jci.insight.120402
                6124439
                29925695
                86a567d2-d12b-4b3e-837a-14d6b19495f9
                © 2018
                History

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