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Neurofibromatosis Type 1: Future Directions (Where Do We Go from Here?)

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Neurofibromatosis Type 1

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Abstract

Two decades of modern molecular research on NF1 has provided unprecedented advances in our understanding of the neurofibromatosis type 1 gene, its protein neurofibromin, and its functions in the complexity that defines this disease. Despite this, the translation of this information into significant patient care enhancement has lagged. Today, the field is on the cusp of overturning this delay with the revolutionary breadth and depth of research findings that will in the near future culminate in the availability of meaningful new therapies for many aspects of NF1 disease. In so doing, the promise held by the cloning of the NF1 gene and its utilization in the development of physiologically relevant animal models will be fulfilled.

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References

  • Acosta MT, Gioia GA, Silva AJ (2006) Neurofibromatosis type 1: new insights into neurocognitive issues. Curr Neurol Neurosci Rep 6:136–143

    Article  PubMed  CAS  Google Scholar 

  • Amlin-Van Schaick J, Kim S, Broman KW, Reilly KM (2012a) Scram1 is a modifier of spinal cord resistance for astrocytoma on mouse Chr 5. Mamm Genome 23:277–285

    Article  PubMed  CAS  Google Scholar 

  • Amlin-Van Schaick JC, Kim S, DiFabio C, Lee MH, Broman KW, Reilly KM (2012b) Arlm1 is a male-specific modifier of astrocytoma resistance on mouse Chr 12. Neuro Oncol 14:160–174

    Article  PubMed  CAS  Google Scholar 

  • Bajenaru ML, Hernandez MR, Perry A, Zhu Y, Parada LF, Garbow JR, Gutmann DH (2003) Optic nerve glioma in mice requires astrocyte Nf1 gene inactivation and Nf1 brain heterozygosity. Cancer Res 63:8573–8577

    PubMed  CAS  Google Scholar 

  • Ballester R, Marchuk D, Boguski M, Saulino A, Letcher R, Wigler M, Collins F (1990) The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 63:851–859

    Article  PubMed  CAS  Google Scholar 

  • Bausch B, Koschker AC, Fassnacht M, Stoevesandt J, Hoffmann MM, Eng C, Allolio B, Neumann HP (2006) Comprehensive mutation scanning of NF1 in apparently sporadic cases of pheochromocytoma. J Clin Endocrinol Metab 91:3478–3481

    Article  PubMed  CAS  Google Scholar 

  • Bernards A, Snijders AJ, Hannigan GE, Murthy AE, Gusella JF (1993) Mouse neurofibromatosis type 1 cDNA sequence reveals high degree of conservation of both coding and non-coding mRNA segments. Hum Mol Genet 2:645–650

    Article  PubMed  CAS  Google Scholar 

  • Bodempudi V, Yamoutpoor F, Pan W, Dudek AZ, Esfandyari T, Piedra M, Babovick-Vuksanovic D, Woo RA, Mautner VF, Kluwe L et al (2009) Ral overactivation in malignant peripheral nerve sheath tumors. Mol Cell Biol 29:3964–3974

    Article  PubMed  CAS  Google Scholar 

  • Bollag G, Clapp DW, Shih S, Adler F, Zhang YY, Thompson P, Lange BJ, Freedman MH, McCormick F, Jacks T et al (1996) Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells. Nat Genet 12:144–148

    Article  PubMed  CAS  Google Scholar 

  • Brannan CI, Perkins AS, Vogel KS, Ratner N, Nordlund ML, Reid SW, Buchberg AM, Jenkins NA, Parada LF, Copeland NG (1994) 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

    Article  PubMed  CAS  Google Scholar 

  • Brown JA, Diggs-Andrews KA, Gianino SM, Gutmann DH (2012) Neurofibromatosis-1 heterozygosity impairs CNS neuronal morphology in a cAMP/PKA/ROCK-dependent manner. Mol Cell Neurosci 49:13–22

    Article  PubMed  CAS  Google Scholar 

  • Buchberg AM, Cleveland LS, Jenkins NA, Copeland NG (1990) Sequence homology shared by neurofibromatosis type-1 gene and IRA-1 and IRA-2 negative regulators of the RAS cyclic AMP pathway. Nature 347:291–294

    Article  PubMed  CAS  Google Scholar 

  • Cacev T, Radosevic S, Spaventi R, Pavelic K, Kapitanovic S (2005) NF1 gene loss of heterozygosity and expression analysis in sporadic colon cancer. Gut 54:1129–1135

    Article  PubMed  CAS  Google Scholar 

  • Cawthon RM, Weiss R, Xu GF, Viskochil D, Culver M, Stevens J, Robertson M, Dunn D, Gesteland R, O'Connell P et al (1990) A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell 62:193–201

    Article  PubMed  CAS  Google Scholar 

  • Chen J, McKay RM, Parada LF (2012) Malignant glioma: lessons from genomics, mouse models, and stem cells. Cell 149:36–47

    Article  PubMed  CAS  Google Scholar 

  • Cichowski K, Shih TS, Schmitt E, Santiago S, Reilly K, McLaughlin ME, Bronson RT, Jacks T (1999) Mouse models of tumor development in neurofibromatosis type 1. Science 286:2172–2176

    Article  PubMed  CAS  Google Scholar 

  • Dasgupta B, Yi Y, Chen DY, Weber JD, Gutmann DH (2005) Proteomic analysis reveals hyperactivation of the mammalian target of rapamycin pathway in neurofibromatosis 1-associated human and mouse brain tumors. Cancer Res 65:2755–2760

    Article  PubMed  CAS  Google Scholar 

  • De Raedt T, Walton Z, Yecies JL, Li D, Chen Y, Malone CF, Maertens O, Jeong SM, Bronson RT, Lebleu V et al (2011) Exploiting cancer cell vulnerabilities to develop a combination therapy for ras-driven tumors. Cancer Cell 20:400–413

    Article  PubMed  Google Scholar 

  • Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB et al (2008) Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455:1069–1075

    Article  PubMed  CAS  Google Scholar 

  • Elefteriou F, Benson MD, Sowa H, Starbuck M, Liu X, Ron D, Parada LF, Karsenty G (2006) ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae. Cell Metab 4:441–451

    Article  PubMed  CAS  Google Scholar 

  • Guo HF, Tong J, Hannan F, Luo L, Zhong Y (2000) A neurofibromatosis-1-regulated pathway is required for learning in Drosophila. Nature 403:895–898

    Article  PubMed  CAS  Google Scholar 

  • Ho IS, Hannan F, Guo HF, Hakker I, Zhong Y (2007) Distinct functional domains of neurofibromatosis type 1 regulate immediate versus long-term memory formation. J Neurosci 27:6852–6857

    Article  PubMed  CAS  Google Scholar 

  • Huson SM, Harper PS, Compston DA (1988) von Recklinghausen neurofibromatosis. A clinical and population study in south-east Wales. Brain 111(Pt 6):1355–1381

    Article  PubMed  Google Scholar 

  • Hyman SL, Arthur Shores E, North KN (2006) Learning disabilities in children with neurofibromatosis type 1: subtypes, cognitive profile, and attention-deficit-hyperactivity disorder. Dev Med Child Neurol 48:973–977

    Article  PubMed  Google Scholar 

  • Jacks T, Shih TS, Schmitt EM, Bronson RT, Bernards A, Weinberg RA (1994) Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nat Genet 7:353–361

    Article  PubMed  CAS  Google Scholar 

  • Johannessen CM, Reczek EE, James MF, Brems H, Legius E, Cichowski K (2005) The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc Natl Acad Sci USA 102:8573–8578

    Article  PubMed  CAS  Google Scholar 

  • Johnson MR, DeClue JE, Felzmann S, Vass WC, Xu G, White R, Lowy DR (1994) Neurofibromin can inhibit Ras-dependent growth by a mechanism independent of its GTPase-accelerating function. Mol Cell Biol 14:641–645

    PubMed  CAS  Google Scholar 

  • Kalamarides M, Acosta MT, Babovic-Vuksanovic D, Carpen O, Cichowski K, Evans DG, Giancotti F, Hanemann CO, Ingram D, Lloyd AC et al (2012) Neurofibromatosis 2011: a report of the Children’s Tumor Foundation annual meeting. Acta Neuropathol 123:369–380

    Article  PubMed  Google Scholar 

  • Keng VW, Rahrmann EP, Watson AL, Tschida BR, Moertel CL, Jessen WJ, Rizvi TA, Collins MH, Ratner N, Largaespada DA (2012) PTEN and NF1 inactivation in Schwann cells produces a severe phenotype in the peripheral nervous system that promotes the development and malignant progression of peripheral nerve sheath tumors. Cancer Res 72(13):3405–3413

    Article  PubMed  CAS  Google Scholar 

  • Klesse LJ, Parada LF (1998) p21 ras and phosphatidylinositol-3 kinase are required for survival of wild-type and NF1 mutant sensory neurons. J Neurosci 18:10420–10428

    PubMed  CAS  Google Scholar 

  • Kolanczyk M, Kuhnisch J, Kossler N, Osswald M, Stumpp S, Thurisch B, Kornak U, Mundlos S (2008) Modelling neurofibromatosis type 1 tibial dysplasia and its treatment with lovastatin. BMC Med 6:21

    Article  PubMed  Google Scholar 

  • Kuorilehto T, Nissinen M, Koivunen J, Benson MD, Peltonen J (2004) NF1 tumor suppressor protein and mRNA in skeletal tissues of developing and adult normal mouse and NF1-deficient embryos. J Bone Miner Res 19:983–989

    Article  PubMed  CAS  Google Scholar 

  • Le DT, Kong N, Zhu Y, Lauchle JO, Aiyigari A, Braun BS, Wang E, Kogan SC, Le Beau MM, Parada L et al (2004) Somatic inactivation of Nf1 in hematopoietic cells results in a progressive myeloproliferative disorder. Blood 103:4243–4250

    Article  PubMed  CAS  Google Scholar 

  • Lee JS, Padmanabhan A, Shin J, Zhu S, Guo F, Kanki JP, Epstein JA, Look AT (2010) Oligodendrocyte progenitor cell numbers and migration are regulated by the zebrafish orthologs of the NF1 tumor suppressor gene. Hum Mol Genet 19:4643–4653

    Article  PubMed  CAS  Google Scholar 

  • Llaguno SA, Chen J, Kwon CH, Parada LF (2008) Neural and cancer stem cells in tumor suppressor mouse models of malignant astrocytoma. Cold Spring Harb Symp Quant Biol 73:421–426

    Article  PubMed  CAS  Google Scholar 

  • Martin GA, Viskochil D, Bollag G, McCabe PC, Crosier WJ, Haubruck H, Conroy L, Clark R, O'Connell P, Cawthon RM et al (1990) The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell 63:843–849

    Article  PubMed  CAS  Google Scholar 

  • North K, Joy P, Yuille D, Cocks N, Mobbs E, Hutchins P, McHugh K, de Silva M (1994) Specific learning disability in children with neurofibromatosis type 1: significance of MRI abnormalities. Neurology 44:878–883

    Article  PubMed  CAS  Google Scholar 

  • Padmanabhan A, Lee JS, Ismat FA, Lu MM, Lawson ND, Kanki JP, Look AT, Epstein JA (2009) Cardiac and vascular functions of the zebrafish orthologues of the type I neurofibromatosis gene NFI. Proc Natl Acad Sci USA 106:22305–22310

    Article  PubMed  CAS  Google Scholar 

  • Parada LF, Kwon CH, Zhu Y (2005) Modeling neurofibromatosis type 1 tumors in the mouse for therapeutic intervention. Cold Spring Harb Symp Quant Biol 70:173–176

    Article  PubMed  CAS  Google Scholar 

  • Silva AJ, Frankland PW, Marowitz Z, Friedman E, Lazlo G, Cioffi D, Jacks T, Bourtchuladze R (1997) A mouse model for the learning and memory deficits associated with neurofibromatosis type I. Nat Genet 15:281–284

    Article  PubMed  CAS  Google Scholar 

  • TCGAR Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068

    Article  Google Scholar 

  • The I, Hannigan GE, Cowley GS, Reginald S, Zhong Y, Gusella JF, Hariharan IK, Bernards A (1997) Rescue of a Drosophila NF1 mutant phenotype by protein kinase A. Science 276:791–794

    Article  PubMed  CAS  Google Scholar 

  • Tong J, Hannan F, Zhu Y, Bernards A, Zhong Y (2002) Neurofibromin regulates G protein-stimulated adenylyl cyclase activity. Nat Neurosci 5:95–96

    Article  PubMed  CAS  Google Scholar 

  • Vogel KS, Klesse LJ, Velasco-Miguel S, Meyers K, Rushing EJ, Parada LF (1999) Mouse tumor model for neurofibromatosis type 1. Science 286:2176–2179

    Article  PubMed  CAS  Google Scholar 

  • Wallace MR, Marchuk DA, Andersen LB, Letcher R, Odeh HM, Saulino AM, Fountain JW, Brereton A, Nicholson J, Mitchell AL et al (1990) Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 249(4965):181–186

    Article  PubMed  CAS  Google Scholar 

  • Wang W, Nyman JS, Ono K, Stevenson DA, Yang X, Elefteriou F (2011) Mice lacking Nf1 in osteochondroprogenitor cells display skeletal dysplasia similar to patients with neurofibromatosis type I. Hum Mol Genet 20:3910–3924

    Article  PubMed  CAS  Google Scholar 

  • Xu GF, O'Connell P, Viskochil D, Cawthon R, Robertson M, Culver M, Dunn D, Stevens J, Gesteland R, White R et al (1990) The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 62:599–608

    Article  PubMed  CAS  Google Scholar 

  • Yang FC, Ingram DA, Chen S, Zhu Y, Yuan J, Li X, Yang X, Knowles S, Horn W, Li Y et al (2008) Nf1-dependent tumors require a microenvironment containing Nf1+/– and c-kit-dependent bone marrow. Cell 135:437–448

    Article  PubMed  CAS  Google Scholar 

  • Zhu Y, Romero MI, Ghosh P, Ye Z, Charnay P, Rushing EJ, Marth JD, Parada LF (2001) Ablation of NF1 function in neurons induces abnormal development of cerebral cortex and reactive gliosis in the brain. Genes Dev 15:859–876

    Article  PubMed  CAS  Google Scholar 

  • Zhu Y, Ghosh P, Charnay P, Burns DK, Parada LF (2002) Neurofibromas in NF1: Schwann cell origin and role of tumor environment. Science 296:920–922

    Article  PubMed  CAS  Google Scholar 

  • Zhu Y, Harada T, Liu L, Lush ME, Guignard F, Harada C, Burns DK, Bajenaru ML, Gutmann DH, Parada LF (2005) Inactivation of NF1 in CNS causes increased glial progenitor proliferation and optic glioma formation. Development 132:5577–5588

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

LFP is Professor and Chairperson of the Department of Development Biology and holds the Diana and Richard C. Strauss Distinguished Chair in Developmental Biology. He is an American Cancer Society Professor and is supported by grants from the NCI, NINDS, CPRIT, the Simons Foundation, and the Goldhirsh Foundation. LFP thanks Renée M. McKay for assistance with the manuscript, and apologizes for inadvertent omission of a particular topic or reference.

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Authors and Affiliations

  1. Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Luis F. Parada

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  1. Luis F. Parada
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Correspondence to Luis F. Parada .

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Editors and Affiliations

  1. School of Medicine, Institute of Medical Genetics, Cardiff University, Heath Park Campus, Cardiff, 144XN, United Kingdom

    Meena Upadhyaya

  2. School of Medicine, Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff, CF14 4XN, United Kingdom

    David N. Cooper

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Parada, L.F. (2012). Neurofibromatosis Type 1: Future Directions (Where Do We Go from Here?). In: Upadhyaya, M., Cooper, D. (eds) Neurofibromatosis Type 1. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-32864-0_44

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