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PLOS ONE  2014 

Nf2/Merlin Controls Spinal Cord Neural Progenitor Function in a Rac1/ErbB2-Dependent Manner

DOI: 10.1371/journal.pone.0097320

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Objective Individuals with the neurofibromatosis type 2 (NF2) cancer predisposition syndrome develop spinal cord glial tumors (ependymomas) that likely originate from neural progenitor cells. Whereas many spinal ependymomas exhibit indolent behavior, the only treatment option for clinically symptomatic tumors is surgery. In this regard, medical therapies are unfortunately lacking due to an incomplete understanding of the critical growth control pathways that govern the function of spinal cord (SC) neural progenitor cells (NPCs). Methods To identify potential therapeutic targets for these tumors, we leveraged primary mouse Nf2-deficient spinal cord neural progenitor cells. Results We demonstrate that the Nf2 protein, merlin, negatively regulates spinal neural progenitor cell survival and glial differentiation in an ErbB2-dependent manner, and that NF2-associated spinal ependymomas exhibit increased ErbB2 activation. Moreover, we show that Nf2-deficient SC NPC ErbB2 activation results from Rac1-mediated ErbB2 retention at the plasma membrane. Significance Collectively, these findings establish ErbB2 as a potential rational therapeutic target for NF2-associated spinal ependymoma.


[1]  Louis DN, Ohgaki H, Wiestler OD, Cavanee WK (2007) WHO Classification of Tumours of the Central Nervous System (IARC WHO Classification of Tumours). International Agency for Research on Cancer, Lyon.
[2]  Johnson RA, Wright KD, Poppleton H, Mohankumar KM, Finkelstein D, et al. (2010) Cross-species genomics matches driver mutations and cell compartments to model ependymoma. Nature 7306: 632–636. doi: 10.1038/nature09173
[3]  Taylor MD, Poppleton H, Fuller C, Su X, Liu Y, et al. (2005) Radial glial cells are candidate stem cells of ependymoma. Cancer Cell 4: 323–335. doi: 10.1016/j.ccr.2005.09.001
[4]  Milde T, Hielscher T, Witt H, Kool M, Mack SC, et al. (2012) Nestin expression identifies ependymoma patients with poor outcome. Brain Pathol 6: 848–860. doi: 10.1111/j.1750-3639.2012.00600.x
[5]  Moynihan T (2003) Ependymal Tumors. Current Treatment Options in Oncology 4: 517–523. doi: 10.1007/s11864-003-0052-5
[6]  Ebert C, Haken M, Meyer-Puttlitz B, Wiestler OD, Reifenberger G, et al. (1999) Molecular genetic analysis of ependymal tumors: NF2 mutations and chromosome 22q loss occur preferentially in intramedullary spinal ependymomas. American Journal of Pathology 155: 627–632. doi: 10.1016/s0002-9440(10)65158-9
[7]  Mautner VF, Tatagiba M, Lindenau M, Fünsterer C, Pulst SM, et al. (1995) Spinal tumors in patients with neurofibromatosis type 2: MR imaging study of frequency, multiplicity, and variety. AJR Am J Roentgenol 165: 951–955. doi: 10.2214/ajr.165.4.7676998
[8]  Plotkin SR, O'Donnell CC, Curry WT, Bove CM, MacCollin M, et al. (2011) Spinal ependymomas in neurofibromatosis Type 2: a retrospective analysis of 55 patients. J Neurosurg Spine 4: 543–547. doi: 10.3171/2010.11.spine10350
[9]  Gutmann DH, Giordano MJ, Fishback AS, Guha A (1997) Loss of merlin expression in sporadic meningiomas, ependymomas and schwannomas. Neurology 1: 267–270. doi: 10.1212/wnl.49.1.267
[10]  Begnami MD, Palau M, Rushing EJ, Santi M, Quezado M (2007) Evaluation of NF2 gene deletion in sporadic schwannomas, meningiomas, and ependymomas by chromogenic in situ hybridization. Hum Pathol 9: 1345–1350. doi: 10.1177/1066896906299128
[11]  Rubio MP, Correa KM, Ramesh V, MacCollin MM, Jacoby LB, et al. (1994) Analysis of the neurofibromatosis 2 gene in human ependymomas and astrocytomas. Cancer Res 1: 45–47.
[12]  Singh PK, Gutmann DH, Fuller CE, Newsham IF, Perry A (2002) Differential involvement of protein 4.1 family members DAL-1 and NF2 in intracranial and intraspinal ependymomas. Mod Pathol 5: 526–531. doi: 10.1038/modpathol.3880558
[13]  Giovannini M, Robanus-Maandag E, Van der Valk M, Niwa-Kawakita M, Abramowski V, et al. (2000) Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2. Genes Dev 13: 1617–1630.
[14]  Dasgupta B, Gutmann DH (2005) Neurofibromin regulates neural stem cell proliferation, survival, and astroglial differentiation in vitro and in vivo. J Neurosci 23: 5584–5594. doi: 10.1523/jneurosci.4693-04.2005
[15]  Uhlmann EJ, Li W, Scheidenhelm DK, Gau CL, Tamanoi F, et al. (2004) Loss of tuberous sclerosis complex 1 (Tsc1) expression results in increased Rheb/S6K pathway signaling important for astrocyte cell size regulation. Glia 47: 180–188. doi: 10.1002/glia.20036
[16]  Lee DY, Yeh TH, Emnett RJ, White CR, Gutmann DH (2010) Neurofibromatosis-1 regulates neuroglial progenitor proliferation and glial differentiation in a brain region-specific manner. Genes Dev 20: 2317–2329. doi: 10.1101/gad.1957110
[17]  Houshmandi SS, Emnett RJ, Giovannini M, Gutmann DH (2009) The neurofibromatosis 2 protein, merlin, regulates glial cell growth in an ErbB2- and Src-dependent manner. Mol Cell Biol 6: 1472–1486. doi: 10.1128/mcb.01392-08
[18]  Kaul A, Chen YH, Emnett RJ, Dahiya S, Gutmann DH (2012) Pediatric glioma-associated KIAA1549: BRAF expression regulates neuroglial cell growth in a cell type-specific and mTOR-dependent manner. Genes Dev 23: 2561–2566. doi: 10.1101/gad.200907.112
[19]  Hegedus B, Dasgupta B, Shin JE, Emnett RJ, Hart-Mahon EK, et al. (2007) Neurofibromatosis-1 regulates neuronal and glial cell differentiation from neuroglial progenitors in vivo by both cAMP- and Ras-dependent mechanisms. Cell Stem Cell 4: 443–457. doi: 10.1016/j.stem.2007.07.008
[20]  Bourn D, Evans G, Mason S, Tekes S, Trueman L, et al. (1995) Eleven novel mutations in the NF2 tumour suppressor gene. Hum Genet 5: 572–574. doi: 10.1007/bf00223872
[21]  Sherman L, Xu HM, Geist RT, Saporito-Irwin S, Howells N, et al. (1997) Interdomain binding mediates tumor growth suppression by the NF2 gene product. Oncogene 20: 2505–2509. doi: 10.1038/sj.onc.1201418
[22]  Schmitz KJ, Grabellus F, Callies R, Otterbach F, Wohlschlaeger J, et al. (2005) High expression of focal adhesion kinase (p125FAK) in node-negative breast cancer is related to overexpression of HER-2/neu and activated Akt kinase but does not predict outcome. Breast Cancer Research 7: 194–203.
[23]  Striedinger K, VandenBerg SR, Baia GS, McDermott MW, Gutmann DH, et al. (2008) The neurofibromatosis 2 tumor suppressor gene product, merlin, regulates human meningioma cell growth by signaling through YAP. Neoplasia 11: 1204–1212.
[24]  James MF, Han S, Polizzano C, Plotkin SR, Manning BD, et al. (2009) NF2/merlin is a novel negative regulator of mTOR complex 1, and activation of mTORC1 is associated with meningioma and schwannoma growth. Mol Cell Biol 15: 4250–4261. doi: 10.1128/mcb.01581-08
[25]  Curto M, Cole BK, Lallemand D, Liu CH, McClatchey AI (2007) Contact-dependent inhibition of EGFR signaling by Nf2/Merlin. J Cell Biol 5: 893–903. doi: 10.1083/jcb.200703010
[26]  Gilbertson RJ, Bentley L, Hernan R, Junttila TT, Frank AJ, et al. (2002) ERBB receptor signaling promotes ependymoma cell proliferation and represents a potential novel therapeutic target for this disease. Clin Cancer Res 10: 3054–64.
[27]  Bush ML, Burns SS, Oblinger J, Davletova S, Chang LS, et al. (2012) Treatment of vestibular schwannoma cells with ErbB inhibitors. Otol Neurotol 2: 244–257. doi: 10.1097/mao.0b013e31823e287f
[28]  Ahmad ZK, Brown CM, Cueva RA, Ryan AF, Doherty JK (2011) ErbB expression, activation, and inhibition with lapatinib and tyrphostin (AG825) in human vestibular schwnnomas. Otol Neurotol 5: 841–847. doi: 10.1097/mao.0b013e31821f7d88
[29]  Xu HM, Gutmann DH (1998) Merlin differentially associates with the microtubule and actin cytoskeleton. J Neurosci Res 3: 403–415. doi: 10.1002/(sici)1097-4547(19980201)51:3<403::aid-jnr13>;2-7
[30]  Manchanda N, Lyubimova A, Ho HY, James MF, Gusella JF, et al. (2005) The NF2 tumor suppressor Merlin and the ERM proteins interact with N-WASP and regulate its actin polymerization function. J Biol Chem 280: 12517–12522. doi: 10.1074/jbc.c400583200
[31]  Manchanda PK, Jones GN, Lee AA, Pringle DR, Zhang M, et al. (2013) Rac1 is required for Prkar1a-mediated Nf2 suppression in Schwann cell tumors. Oncogene 30: 3491–3499. doi: 10.1038/onc.2012.374
[32]  Wong HK, Shimizu A, Kirkpatrick ND, Garkavtsev I, Chan AW, et al. (2012) Merlin/NF2 regulates angiogenesis in schwannomas through a Rac1/semaphorin 3F-dependent mechanism. Neoplasia 2: 84–94.
[33]  Bosco EE, Nakai Y, Hennigan RF, Ratner N, Zheng Y (2010) NF2-deficient cells depend on the Rac1-canonical Wnt signaling pathway to promote the loss of contact inhibition of proliferation. Oncogene 7: 2540–2549. doi: 10.1038/onc.2010.20
[34]  Yi C, Troutman S, Fera D, Stemmer-Rachamimov A, Avila JL, et al. (2011) A tight junction-associated Merlin-angiomotin complex mediates Merlin's regulation of mitogenic signaling and tumor suppressive functions. Cancer Cell 4: 527–540. doi: 10.1016/j.ccr.2011.02.017
[35]  Cole BK, Curto M, Chan AW, McClatchey AI (2008) Localization to the cortical cytoskeleton is necessary for Nf2/merlin-dependent epidermal growth factor receptor silencing. Mol Cell Biol 4: 1274–1284. doi: 10.1128/mcb.01139-07
[36]  Morris ZS, McClatchey AI (2009) Aberrant epithelial morphology and persistent epidermal growth factor receptor signaling in a mouse model of renal carcinoma. Proc Natl Acad Sci USA 24: 9767–9772. doi: 10.1073/pnas.0902031106
[37]  Ghashghaei HT, Weimer JM, Schmid RS, Yokota Y, McCarthy KD, et al. (2007) Reinduction of ErbB2 in astrocytes promotes radial glial progenitor identity in adult cerebral cortex. Genes Dev 24: 3258–3271. doi: 10.1101/gad.1580407
[38]  Schmid RS, McGrath B, Berechid BE, Boyles B, Marchionni M, et al. (2003) Neuregulin 1-erbB2 signaling is required for the establishment of radial glia and their transformation into astrocytes in cerebral cortex. Proc Natl Acad Sci USA 7: 4251–4256. doi: 10.1073/pnas.0630496100
[39]  Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 7216: 1061–1068. doi: 10.1038/nature11903
[40]  Ritch PS, Carroll SL, Sontheimer H (2005) Neuregulin-1 enhances survival of human astrocytic glioma cells. Glia 3: 217–228. doi: 10.1002/glia.20197


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