1. NCCU Academic Hub
  2. Publications
  3. College of Science
  4. Theses
  5. Item

Publications-Theses

Article View/Open

Publication Export

Google ScholarTM

NCCU Library

Citation Infomation

Related Publications in TAIR

題名 BMP4 於神經肌肉系統生理功能之探討
The physiological functions of BMP4 in the neuromuscular system
作者 周慧茹
Chou, Hui Ju
貢獻者 王培育
Wang, Pei Yu
周慧茹
Chou, Hui Ju
關鍵詞 骨形成蛋白-4
神經肌肉系統
興奮性毒殺作用
BMP4
neuromuscular junction
excitotoxicity
日期 2011
上傳時間 4-Sep-2013 15:06:10 (UTC+8)
摘要 骨形成蛋白 (bone morphogenetic proteins, BMPs) 屬於TGF家族的成員，過去的研究指出BMPs對神經系統的發育及維持非常的重要，並且會參與調控突觸的形成。然而，在哺乳類動物的研究中，BMPs在神經肌肉系統中所調控的生理功能仍未完全了解。本實驗室初步的研究資料顯示BMPs的type II受體 (bone morphogenetic protein type II receptor, BMPRII) 會表現在神經與肌肉接合處 (neuromuscular junction, NMJ) ，而從本論文中的免疫染色實驗結果觀察到骨形成蛋白-4 (BMP4) 會表現在肌肉及許旺細胞上，且BMP4與乙醯膽鹼受體 (acetylcholine receptors, AChRs) 有colocalization的現象。由double nerve ligations的實驗觀察到BMP4會堆積在打結處的兩端，顯示BMP4可能是由肌肉或許旺細胞分泌後送進運動神經元之軸突內運輸，其方向為雙向性運輸，而利用Q-PCR mRNA定量實驗發現BMP4 mRNA在double-ligated之坐骨神經中表現量下降，但在肌肉中表現量則顯著增加。
由上述實驗顯示肌肉細胞為BMP4主要來源之ㄧ，利用NG108-15神經細胞及C2C12肌肉細胞培養，我們發現BMP4 mRNA在C2C12肌小管上有高度表現，相反地在分化後的NG108-15神經細胞上表現量極少，而BMP4的mRNA及protein在C2C12肌肉上的表現量則受到神經衍生蛋白Agrin的調控。此外我們亦發現來自於肌肉的BMP4則會保護分化後的NG108-15神經細胞對抗Glutamate所誘導的細胞死亡反應。綜合這些結果，我們認為BMP4主要來自於運動神經元之周邊的肌肉及許旺細胞，其可能會參與調控運動神經元的存活機制。
Bone morphogenetic proteins (BMPs), members of the TGF superfamily, have been shown to play important roles in the development of nervous system including neuronal survival and synaptogenesis. However, the physiological functions of BMP signaling at the mammalian neuromuscular system are not well understood. Our preliminary data showed that proteins of the type II bone morphogenetic receptors (BMPRII) were specifically expressed in nerve terminals at neuromuscular junctions. In this study, we found that proteins of bone morphogenetic protein-4 (BMP4) were detected at Schwann cells and colocalized with postsynaptic acetylcholine receptors (AChRs) in skeletal muscle fibers. In double-ligated nerves, BMP4 proteins were accumulated at the proximal and distal portions of the axons, suggesting that Schwann cell- and muscle fiber-derived BMP4 proteins were anterogradely and retrogradely transported by motor neurons. Additionally, BMP4 mRNA was significantly up-regulated in the muscle but down-regulated in ligated sciatic nerves.
The physiological functions of BMP4 in the neuromuscular system were further examined in vitro. We found that mRNA of BMP4 was highly expressed in differentiated C2C12 muscle cells, but it was barely detectable in NG108-5 neurons. The expression of BMP4 mRNA and protein in C2C12 muscle cells were upregulated when the motor neuron-derived factor, agrin, was presented in the culture. Moreover, muscle-derived BMP4 could protect NG108-5 neurons from glutamate-induced excitotoxicity. These results together suggest that BMP4 is a peripheral-derived factor that may regulate the survival of motor neurons.
參考文獻 Aberle H, Haghighi AP, Fetter RD, McCabe BD, Magalhaes TR, Goodman CS (2002) wishful thinking encodes a BMP type II receptor that regulates synaptic growth in Drosophila. Neuron 33:545-558.
An MC, Lin W, Yang J, Dominguez B, Padgett D, Sugiura Y, Aryal P, Gould TW, Oppenheim RW, Hester ME, Kaspar BK, Ko CP, Lee KF (2010) Acetylcholine negatively regulates development of the neuromuscular junction through distinct cellular mechanisms. Proceedings of the National Academy of Sciences of the United States of America 107:10702-10707.
Arkell R, Beddington RS (1997) BMP-7 influences pattern and growth of the developing hindbrain of mouse embryos. Development 124:1-12.
Ball RW, Warren-Paquin M, Tsurudome K, Liao EH, Elazzouzi F, Cavanagh C, An BS, Wang TT, White JH, Haghighi AP (2010) Retrograde BMP signaling controls synaptic growth at the NMJ by regulating trio expression in motor neurons. Neuron 66:536-549.
Barone FC, Irving EA, Ray AM, Lee JC, Kassis S, Kumar S, Badger AM, White RF, McVey MJ, Legos JJ, Erhardt JA, Nelson AH, Ohlstein EH, Hunter AJ, Ward K, Smith BR, Adams JL, Parsons AA (2001) SB 239063, a second-generation p38 mitogen-activated protein kinase inhibitor, reduces brain injury and neurological deficits in cerebral focal ischemia. The Journal of pharmacology and experimental therapeutics 296:312-321.
Bensimon G, Lacomblez L, Meininger V (1994) A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. The New England journal of medicine 330:585-591.
Beppu H, Minowa O, Miyazono K, Kawabata M (1997) cDNA cloning and genomic organization of the mouse BMP type II receptor. Biochemical and biophysical research communications 235:499-504.
Borges LS, Yechikhov S, Lee YI, Rudell JB, Friese MB, Burden SJ, Ferns MJ (2008) Identification of a motif in the acetylcholine receptor beta subunit whose phosphorylation regulates rapsyn association and postsynaptic receptor localization. The Journal of neuroscience : the official journal of the Society for Neuroscience 28:11468-11476.
Bragdon B, Moseychuk O, Saldanha S, King D, Julian J, Nohe A (2011) Bone morphogenetic proteins: a critical review. Cellular signalling 23:609-620.
Brandon EP, Lin W, D`Amour KA, Pizzo DP, Dominguez B, Sugiura Y, Thode S, Ko CP, Thal LJ, Gage FH, Lee KF (2003) Aberrant patterning of neuromuscular synapses in choline acetyltransferase-deficient mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 23:539-549.
Caroscio JT, Mulvihill MN, Sterling R, Abrams B (1987) Amyotrophic lateral sclerosis. Its natural history. Neurologic clinics 5:1-8.
Chen X, Weisberg E, Fridmacher V, Watanabe M, Naco G, Whitman M (1997) Smad4 and FAST-1 in the assembly of activin-responsive factor. Nature 389:85-89.
Chiang C, Litingtung Y, Lee E, Young KE, Corden JL, Westphal H, Beachy PA (1996) Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383:407-413.
Choi DW (1987) Ionic dependence of glutamate neurotoxicity. The Journal of neuroscience : the official journal of the Society for Neuroscience 7:369-379.
Ericson J, Morton S, Kawakami A, Roelink H, Jessell TM (1996) Two critical periods of Sonic Hedgehog signaling required for the specification of motor neuron identity. Cell 87:661-673.
Feng Z, Ko CP (2008) Schwann cells promote synaptogenesis at the neuromuscular junction via transforming growth factor-beta1. The Journal of neuroscience : the official journal of the Society for Neuroscience 28:9599-9609.
Ferayorni AJ, Gunville CF, Grow WA (2004) Nicotine decreases agrin signaling and acetylcholine receptor clustering in C2C12 myotube culture. Journal of neurobiology 60:51-60.
Fischer AJ, Schmidt M, Omar G, Reh TA (2004) BMP4 and CNTF are neuroprotective and suppress damage-induced proliferation of Muller glia in the retina. Molecular and cellular neurosciences 27:531-542.
Foletta VC, Lim MA, Soosairajah J, Kelly AP, Stanley EG, Shannon M, He W, Das S, Massague J, Bernard O (2003) Direct signaling by the BMP type II receptor via the cytoskeletal regulator LIMK1. The Journal of cell biology 162:1089-1098.
Friedman B, Scherer SS, Rudge JS, Helgren M, Morrisey D, McClain J, Wang DY, Wiegand SJ, Furth ME, Lindsay RM, et al. (1992) Regulation of ciliary neurotrophic factor expression in myelin-related Schwann cells in vivo. Neuron 9:295-305.
Fuller ML, DeChant AK, Rothstein B, Caprariello A, Wang R, Hall AK, Miller RH (2007) Bone morphogenetic proteins promote gliosis in demyelinating spinal cord lesions. Annals of neurology 62:288-300.
Funakoshi H, Belluardo N, Arenas E, Yamamoto Y, Casabona A, Persson H, Ibanez CF (1995) Muscle-derived neurotrophin-4 as an activity-dependent trophic signal for adult motor neurons. Science 268:1495-1499.
Gautam M, Noakes PG, Moscoso L, Rupp F, Scheller RH, Merlie JP, Sanes JR (1996) Defective neuromuscular synaptogenesis in agrin-deficient mutant mice. Cell 85:525-535.
Gesemann M, Denzer AJ, Ruegg MA (1995) Acetylcholine receptor-aggregating activity of agrin isoforms and mapping of the active site. The Journal of cell biology 128:625-636.
Glass DJ, DeChiara TM, Stitt TN, DiStefano PS, Valenzuela DM, Yancopoulos GD (1996a) The receptor tyrosine kinase MuSK is required for neuromuscular junction formation and is a functional receptor for agrin. Cold Spring Harbor symposia on quantitative biology 61:435-444.
Glass DJ, Bowen DC, Stitt TN, Radziejewski C, Bruno J, Ryan TE, Gies DR, Shah S, Mattsson K, Burden SJ, DiStefano PS, Valenzuela DM, DeChiara TM, Yancopoulos GD (1996b) Agrin acts via a MuSK receptor complex. Cell 85:513-523.
Gould TW, Enomoto H (2009) Neurotrophic modulation of motor neuron development. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry 15:105-116.
Guha U, Gomes WA, Samanta J, Gupta M, Rice FL, Kessler JA (2004) Target-derived BMP signaling limits sensory neuron number and the extent of peripheral innervation in vivo. Development 131:1175-1186.
Hamburger V (1958) Regression versus peripheral control of differentiation in motor hypoplasia. The American journal of anatomy 102:365-409.
Heath PR, Shaw PJ (2002) Update on the glutamatergic neurotransmitter system and the role of excitotoxicity in amyotrophic lateral sclerosis. Muscle & nerve 26:438-458.
Ishii DN (1989) Relationship of insulin-like growth factor II gene expression in muscle to synaptogenesis. Proceedings of the National Academy of Sciences of the United States of America 86:2898-2902.
Jennings CG, Dyer SM, Burden SJ (1993) Muscle-specific trk-related receptor with a kringle domain defines a distinct class of receptor tyrosine kinases. Proceedings of the National Academy of Sciences of the United States of America 90:2895-2899.
Jessell TM (2000) Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nature reviews Genetics 1:20-29.
Jiang Y, Zhang M, Koishi K, McLennan IS (2000a) TGF-beta 2 attenuates the injury-induced death of mature motoneurons. Journal of neuroscience research 62:809-813.
Jiang Y, McLennan IS, Koishi K, Hendry IA (2000b) Transforming growth factor-beta 2 is anterogradely and retrogradely transported in motoneurons and up-regulated after nerve injury. Neuroscience 97:735-742.
Kawabata M, Imamura T, Miyazono K (1998) Signal transduction by bone morphogenetic proteins. Cytokine & growth factor reviews 9:49-61.
Kilpatrick TJ, Soilu-Hanninen M (1999) Molecular mechanisms regulating motor neuron development and degeneration. Molecular neurobiology 19:205-228.
Kim N, Burden SJ (2008) MuSK controls where motor axons grow and form synapses. Nature neuroscience 11:19-27.
Kim N, Stiegler AL, Cameron TO, Hallock PT, Gomez AM, Huang JH, Hubbard SR, Dustin ML, Burden SJ (2008) Lrp4 is a receptor for Agrin and forms a complex with MuSK. Cell 135:334-342.
Kretzschmar M, Massague J (1998) SMADs: mediators and regulators of TGF-beta signaling. Current opinion in genetics & development 8:103-111.
Laake JH, Slyngstad TA, Haug FM, Ottersen OP (1995) Glutamine from glial cells is essential for the maintenance of the nerve terminal pool of glutamate: immunogold evidence from hippocampal slice cultures. Journal of neurochemistry 65:871-881.
Labeur M, Paez-Pereda M, Haedo M, Arzt E, Stalla GK (2010) Pituitary tumors: cell type-specific roles for BMP-4. Molecular and cellular endocrinology 326:85-88.
Lanser ME, Fallon JF (1987) Development of the brachial lateral motor column in the wingless mutant chick embryo: motoneuron survival under varying degrees of peripheral load. The Journal of comparative neurology 261:423-434.
Liem KF, Jr., Tremml G, Jessell TM (1997) A role for the roof plate and its resident TGFbeta-related proteins in neuronal patterning in the dorsal spinal cord. Cell 91:127-138.
Liem KF, Jr., Jessell TM, Briscoe J (2000) Regulation of the neural patterning activity of sonic hedgehog by secreted BMP inhibitors expressed by notochord and somites. Development 127:4855-4866.
Liem KF, Jr., Tremml G, Roelink H, Jessell TM (1995) Dorsal differentiation of neural plate cells induced by BMP-mediated signals from epidermal ectoderm. Cell 82:969-979.
Lin W, Dominguez B, Yang J, Aryal P, Brandon EP, Gage FH, Lee KF (2005) Neurotransmitter acetylcholine negatively regulates neuromuscular synapse formation by a Cdk5-dependent mechanism. Neuron 46:569-579.
Ling KK, Siow NL, Choi RC, Tsim KW (2005) ATP potentiates the formation of AChR aggregate in the co-culture of NG108-15 cells with C2C12 myotubes. FEBS letters 579:2469-2474.
Macpherson PC, Wang X, Goldman D (2011) Myogenin regulates denervation-dependent muscle atrophy in mouse soleus muscle. Journal of cellular biochemistry 112:2149-2159.
Marques G, Bao H, Haerry TE, Shimell MJ, Duchek P, Zhang B, O`Connor MB (2002) The Drosophila BMP type II receptor Wishful Thinking regulates neuromuscular synapse morphology and function. Neuron 33:529-543.
Marti E, Bumcrot DA, Takada R, McMahon AP (1995) Requirement of 19K form of Sonic hedgehog for induction of distinct ventral cell types in CNS explants. Nature 375:322-325.
McCabe BD, Marques G, Haghighi AP, Fetter RD, Crotty ML, Haerry TE, Goodman CS, O`Connor MB (2003) The BMP homolog Gbb provides a retrograde signal that regulates synaptic growth at the Drosophila neuromuscular junction. Neuron 39:241-254.
Misgeld T, Burgess RW, Lewis RM, Cunningham JM, Lichtman JW, Sanes JR (2002) Roles of neurotransmitter in synapse formation: development of neuromuscular junctions lacking choline acetyltransferase. Neuron 36:635-648.
Nilsson EE, Skinner MK (2003) Bone morphogenetic protein-4 acts as an ovarian follicle survival factor and promotes primordial follicle development. Biology of reproduction 69:1265-1272.
Nitkin RM, Smith MA, Magill C, Fallon JR, Yao YM, Wallace BG, McMahan UJ (1987) Identification of agrin, a synaptic organizing protein from Torpedo electric organ. The Journal of cell biology 105:2471-2478.
Nohe A, Keating E, Knaus P, Petersen NO (2004) Signal transduction of bone morphogenetic protein receptors. Cellular signalling 16:291-299.
Okada K, Inoue A, Okada M, Murata Y, Kakuta S, Jigami T, Kubo S, Shiraishi H, Eguchi K, Motomura M, Akiyama T, Iwakura Y, Higuchi O, Yamanashi Y (2006) The muscle protein Dok-7 is essential for neuromuscular synaptogenesis. Science 312:1802-1805.
Oppenheim RW, Prevette D, Haverkamp LJ, Houenou L, Yin QW, McManaman J (1993) Biological studies of a putative avian muscle-derived neurotrophic factor that prevents naturally occurring motoneuron death in vivo. Journal of neurobiology 24:1065-1079.
Oppenheim RW, Wiese S, Prevette D, Armanini M, Wang S, Houenou LJ, Holtmann B, Gotz R, Pennica D, Sendtner M (2001) Cardiotrophin-1, a muscle-derived cytokine, is required for the survival of subpopulations of developing motoneurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 21:1283-1291.
Oza J, Yang J, Chen KY, Liu AY (2008) Changes in the regulation of heat shock gene expression in neuronal cell differentiation. Cell stress & chaperones 13:73-84.
Parikh P, Hao Y, Hosseinkhani M, Patil SB, Huntley GW, Tessier-Lavigne M, Zou H (2011) Regeneration of axons in injured spinal cord by activation of bone morphogenetic protein/Smad1 signaling pathway in adult neurons. Proceedings of the National Academy of Sciences of the United States of America 108:E99-107.
Peng TI, Greenamyre JT (1998) Privileged access to mitochondria of calcium influx through N-methyl-D-aspartate receptors. Molecular pharmacology 53:974-980.
Podkowa M, Zhao X, Chow CW, Coffey ET, Davis RJ, Attisano L (2010) Microtubule stabilization by bone morphogenetic protein receptor-mediated scaffolding of c-Jun N-terminal kinase promotes dendrite formation. Molecular and cellular biology 30:2241-2250.
Qi X, Li TG, Hao J, Hu J, Wang J, Simmons H, Miura S, Mishina Y, Zhao GQ (2004) BMP4 supports self-renewal of embryonic stem cells by inhibiting mitogen-activated protein kinase pathways. Proceedings of the National Academy of Sciences of the United States of America 101:6027-6032.
Reist NE, Werle MJ, McMahan UJ (1992) Agrin released by motor neurons induces the aggregation of acetylcholine receptors at neuromuscular junctions. Neuron 8:865-868.
Riethmacher D, Sonnenberg-Riethmacher E, Brinkmann V, Yamaai T, Lewin GR, Birchmeier C (1997) Severe neuropathies in mice with targeted mutations in the ErbB3 receptor. Nature 389:725-730.
Roelink H, Porter JA, Chiang C, Tanabe Y, Chang DT, Beachy PA, Jessell TM (1995) Floor plate and motor neuron induction by different concentrations of the amino-terminal cleavage product of sonic hedgehog autoproteolysis. Cell 81:445-455.
Rothstein JD, Martin LJ, Kuncl RW (1992) Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. The New England journal of medicine 326:1464-1468.
Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW (1995) Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Annals of neurology 38:73-84.
Rothstein JD, Tsai G, Kuncl RW, Clawson L, Cornblath DR, Drachman DB, Pestronk A, Stauch BL, Coyle JT (1990) Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis. Annals of neurology 28:18-25.
Ruegg MA, Bixby JL (1998) Agrin orchestrates synaptic differentiation at the vertebrate neuromuscular junction. Trends in neurosciences 21:22-27.
Ruegg MA, Tsim KW, Horton SE, Kroger S, Escher G, Gensch EM, McMahan UJ (1992) The agrin gene codes for a family of basal lamina proteins that differ in function and distribution. Neuron 8:691-699.
Ruggiu M, Herbst R, Kim N, Jevsek M, Fak JJ, Mann MA, Fischbach G, Burden SJ, Darnell RB (2009) Rescuing Z+ agrin splicing in Nova null mice restores synapse formation and unmasks a physiologic defect in motor neuron firing. Proceedings of the National Academy of Sciences of the United States of America 106:3513-3518.
Russell FD, Koishi K, Jiang Y, McLennan IS (2000) Anterograde axonal transport of glial cell line-derived neurotrophic factor and its receptors in rat hypoglossal nerve. Neuroscience 97:575-580.
Sabo JK, Aumann TD, Merlo D, Kilpatrick TJ, Cate HS (2011) Remyelination is altered by bone morphogenic protein signaling in demyelinated lesions. The Journal of neuroscience : the official journal of the Society for Neuroscience 31:4504-4510.
Salpeter MM, Cooper DL, Levitt-Gilmour T (1986) Degradation rates of acetylcholine receptors can be modified in the postjunctional plasma membrane of the vertebrate neuromuscular junction. The Journal of cell biology 103:1399-1403.
Schelman WR, Andres RD, Sipe KJ, Kang E, Weyhenmeyer JA (2004a) Glutamate mediates cell death and increases the Bax to Bcl-2 ratio in a differentiated neuronal cell line. Brain research Molecular brain research 128:160-169.
Schelman WR, Andres R, Ferguson P, Orr B, Kang E, Weyhenmeyer JA (2004b) Angiotensin II attenuates NMDA receptor-mediated neuronal cell death and prevents the associated reduction in Bcl-2 expression. Brain research Molecular brain research 128:20-29.
Sendtner M, Kreutzberg GW, Thoenen H (1990) Ciliary neurotrophic factor prevents the degeneration of motor neurons after axotomy. Nature 345:440-441.
Sendtner M, Stockli KA, Thoenen H (1992) Synthesis and localization of ciliary neurotrophic factor in the sciatic nerve of the adult rat after lesion and during regeneration. The Journal of cell biology 118:139-148.
Shi Y, Massague J (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113:685-700.
Sieber C, Kopf J, Hiepen C, Knaus P (2009) Recent advances in BMP receptor signaling. Cytokine & growth factor reviews 20:343-355.
Suzuki A, Nishimatsu S, Shoda A, Takebayashi K, Murakami K, Ueno N (1993) Biochemical properties of amphibian bone morphogenetic protein-4 expressed in CHO cells. The Biochemical journal 291 ( Pt 2):413-417.
Tanaka K, Watase K, Manabe T, Yamada K, Watanabe M, Takahashi K, Iwama H, Nishikawa T, Ichihara N, Kikuchi T, Okuyama S, Kawashima N, Hori S, Takimoto M, Wada K (1997) Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 276:1699-1702.
Valenzuela DM, Stitt TN, DiStefano PS, Rojas E, Mattsson K, Compton DL, Nunez L, Park JS, Stark JL, Gies DR, et al. (1995) Receptor tyrosine kinase specific for the skeletal muscle lineage: expression in embryonic muscle, at the neuromuscular junction, and after injury. Neuron 15:573-584.
Wang PY (2006) Novel survival factors with a gender specific twist for motor neurons: a thesis submitted for the degree of Doctor of Philosophy at the University of Otago, Dunedin, New Zealand: University of Otago.
Wang PY, Koishi K, McLennan IS (2007a) BMP6 is axonally transported by motoneurons and supports their survival in vitro. Molecular and cellular neurosciences 34:653-661.
Wang YL, Wang DZ, Nie X, Lei DL, Liu YP, Zhang YJ, Suwa F, Tamada Y, Fang YR, Jin Y (2007b) The role of bone morphogenetic protein-2 in vivo in regeneration of peripheral nerves. The British journal of oral & maxillofacial surgery 45:197-202.
Weatherbee SD, Anderson KV, Niswander LA (2006) LDL-receptor-related protein 4 is crucial for formation of the neuromuscular junction. Development 133:4993-5000.
Weiss JH (2011) Ca permeable AMPA channels in diseases of the nervous system. Frontiers in molecular neuroscience 4:42.
Whitlon DS, Grover M, Tristano J, Williams T, Coulson MT (2007) Culture conditions determine the prevalence of bipolar and monopolar neurons in cultures of dissociated spiral ganglion. Neuroscience 146:833-840.
Wine-Lee L, Ahn KJ, Richardson RD, Mishina Y, Lyons KM, Crenshaw EB, 3rd (2004) Signaling through BMP type 1 receptors is required for development of interneuron cell types in the dorsal spinal cord. Development 131:5393-5403.
Winnier G, Blessing M, Labosky PA, Hogan BL (1995) Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse. Genes & development 9:2105-2116.
Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, Hewick RM, Wang EA (1988) Novel regulators of bone formation: molecular clones and activities. Science 242:1528-1534.
Wrana JL, Attisano L, Wieser R, Ventura F, Massague J (1994) Mechanism of activation of the TGF-beta receptor. Nature 370:341-347.
Wu H, Xiong WC, Mei L (2010) To build a synapse: signaling pathways in neuromuscular junction assembly. Development 137:1017-1033.
Zhang B, Luo S, Wang Q, Suzuki T, Xiong WC, Mei L (2008) LRP4 serves as a coreceptor of agrin. Neuron 60:285-297.
Zhu JJ, Qin Y, Zhao M, Van Aelst L, Malinow R (2002) Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell 110:443-455.
描述 碩士
國立政治大學
神經科學研究所
98754002
100
資料來源 http://thesis.lib.nccu.edu.tw/record/#G0987540021
資料類型 thesis
dc.contributor.advisor 王培育zh_TW
dc.contributor.advisor Wang, Pei Yuen_US
dc.contributor.author (Authors) 周慧茹zh_TW
dc.contributor.author (Authors) Chou, Hui Juen_US
dc.creator (作者) 周慧茹zh_TW
dc.creator (作者) Chou, Hui Juen_US
dc.date (日期) 2011en_US
dc.date.accessioned 4-Sep-2013 15:06:10 (UTC+8)-
dc.date.available 4-Sep-2013 15:06:10 (UTC+8)-
dc.date.issued (上傳時間) 4-Sep-2013 15:06:10 (UTC+8)-
dc.identifier (Other Identifiers) G0987540021en_US
dc.identifier.uri (URI) http://nccur.lib.nccu.edu.tw/handle/140.119/60054-
dc.description (描述) 碩士zh_TW
dc.description (描述) 國立政治大學zh_TW
dc.description (描述) 神經科學研究所zh_TW
dc.description (描述) 98754002zh_TW
dc.description (描述) 100zh_TW
dc.description.abstract (摘要) 骨形成蛋白 (bone morphogenetic proteins, BMPs) 屬於TGF家族的成員，過去的研究指出BMPs對神經系統的發育及維持非常的重要，並且會參與調控突觸的形成。然而，在哺乳類動物的研究中，BMPs在神經肌肉系統中所調控的生理功能仍未完全了解。本實驗室初步的研究資料顯示BMPs的type II受體 (bone morphogenetic protein type II receptor, BMPRII) 會表現在神經與肌肉接合處 (neuromuscular junction, NMJ) ，而從本論文中的免疫染色實驗結果觀察到骨形成蛋白-4 (BMP4) 會表現在肌肉及許旺細胞上，且BMP4與乙醯膽鹼受體 (acetylcholine receptors, AChRs) 有colocalization的現象。由double nerve ligations的實驗觀察到BMP4會堆積在打結處的兩端，顯示BMP4可能是由肌肉或許旺細胞分泌後送進運動神經元之軸突內運輸，其方向為雙向性運輸，而利用Q-PCR mRNA定量實驗發現BMP4 mRNA在double-ligated之坐骨神經中表現量下降，但在肌肉中表現量則顯著增加。
由上述實驗顯示肌肉細胞為BMP4主要來源之ㄧ，利用NG108-15神經細胞及C2C12肌肉細胞培養，我們發現BMP4 mRNA在C2C12肌小管上有高度表現，相反地在分化後的NG108-15神經細胞上表現量極少，而BMP4的mRNA及protein在C2C12肌肉上的表現量則受到神經衍生蛋白Agrin的調控。此外我們亦發現來自於肌肉的BMP4則會保護分化後的NG108-15神經細胞對抗Glutamate所誘導的細胞死亡反應。綜合這些結果，我們認為BMP4主要來自於運動神經元之周邊的肌肉及許旺細胞，其可能會參與調控運動神經元的存活機制。		zh_TW
dc.description.abstract (摘要) Bone morphogenetic proteins (BMPs), members of the TGF superfamily, have been shown to play important roles in the development of nervous system including neuronal survival and synaptogenesis. However, the physiological functions of BMP signaling at the mammalian neuromuscular system are not well understood. Our preliminary data showed that proteins of the type II bone morphogenetic receptors (BMPRII) were specifically expressed in nerve terminals at neuromuscular junctions. In this study, we found that proteins of bone morphogenetic protein-4 (BMP4) were detected at Schwann cells and colocalized with postsynaptic acetylcholine receptors (AChRs) in skeletal muscle fibers. In double-ligated nerves, BMP4 proteins were accumulated at the proximal and distal portions of the axons, suggesting that Schwann cell- and muscle fiber-derived BMP4 proteins were anterogradely and retrogradely transported by motor neurons. Additionally, BMP4 mRNA was significantly up-regulated in the muscle but down-regulated in ligated sciatic nerves.
The physiological functions of BMP4 in the neuromuscular system were further examined in vitro. We found that mRNA of BMP4 was highly expressed in differentiated C2C12 muscle cells, but it was barely detectable in NG108-5 neurons. The expression of BMP4 mRNA and protein in C2C12 muscle cells were upregulated when the motor neuron-derived factor, agrin, was presented in the culture. Moreover, muscle-derived BMP4 could protect NG108-5 neurons from glutamate-induced excitotoxicity. These results together suggest that BMP4 is a peripheral-derived factor that may regulate the survival of motor neurons.		en_US
dc.description.tableofcontents 謝誌...I
中文摘要...II
英文摘要...III
目錄...IV
圖次...VII
縮寫表... VIII
第一章 緒論...1
第一節、 脊髓運動神經元的發育過程...1
一、 脊髓運動神經元早期的發育...1
二、 脊髓運動神經元的構造...2
第二節、 神經肌肉接合處 (neuromuscular junction, NMJ)...3
一、 NMJ的形成...3
二、 Agrin/Lrp4/MuSK/rapsyn 訊息傳遞路徑...4
三、 TGF/BMP訊息傳遞路徑與NMJ之間的關係...6
第三節、 運動神經元的發育與周邊系統之間的關係...7
第四節、 周邊衍生性神經滋養因子...7
一、 肌肉衍生性神經滋養因子...8
二、 許旺細胞衍生性神經滋養因子...8
第五節、 骨形成蛋白家族 (BMP superfamily) 8
一、 骨形成蛋白-4...9
二、 骨形成蛋白-4之受體...10
三、 骨形成蛋白-4之生理功能...11
第六節、 興奮性毒殺作用與運動神經元疾病...11
第七節、 本論文之研究目的...13
第二章 實驗材料與研究方法....14
第一節、 細胞株之培養...14
一、 細胞株之種類及來源...14
二、 細胞培養...14
三、 藥物處理...16
第二節、 實驗動物...17
第三節、 Nerve ligation...17
第四節、 Muscle denervation...18
第五節、 免疫染色法 (immunostaining)...18
一、 免疫組織染色法 (immunohistochemistry)...18
二、 Whole mount soleus muscle及免疫螢光染色法...20
三、 C2C12肌小管之免疫螢光染色及定量分析...20
第六節、 即時定量聚合酶連鎖反應...21
一、 RNA 之萃取...21
二、 互補鏈DNA反轉錄反應...22
三、 即時定量聚合酶連鎖反應...23
第七節、 細胞存活率分析...24
第八節、 統計分析...24
第三章 實驗結果...25
第一節、 BMPRII的表現位置...26
第二節、 BMP4參與調控運動神經元與肌肉之間的機制...27
第三節、 BMP4亦是由許旺細胞所產生並且於運動神經元中運輸...35
第四節、 軸突損傷會影響周邊組織中BMP4的表現...38
第五節、 BMP4可能參與調控運動神經元的存活...40
第四章 討論...46
第五章 結論...50
參考文獻...51
附錄一... IX
附錄二... X		zh_TW
dc.format.extent 1423512 bytes-
dc.format.mimetype application/pdf-
dc.language.iso en_US-
dc.source.uri (資料來源) http://thesis.lib.nccu.edu.tw/record/#G0987540021en_US
dc.subject (關鍵詞) 骨形成蛋白-4zh_TW
dc.subject (關鍵詞) 神經肌肉系統zh_TW
dc.subject (關鍵詞) 興奮性毒殺作用zh_TW
dc.subject (關鍵詞) BMP4en_US
dc.subject (關鍵詞) neuromuscular junctionen_US
dc.subject (關鍵詞) excitotoxicityen_US
dc.title (題名) BMP4 於神經肌肉系統生理功能之探討zh_TW
dc.title (題名) The physiological functions of BMP4 in the neuromuscular systemen_US
dc.type (資料類型) thesisen
dc.relation.reference (參考文獻) Aberle H, Haghighi AP, Fetter RD, McCabe BD, Magalhaes TR, Goodman CS (2002) wishful thinking encodes a BMP type II receptor that regulates synaptic growth in Drosophila. Neuron 33:545-558.
An MC, Lin W, Yang J, Dominguez B, Padgett D, Sugiura Y, Aryal P, Gould TW, Oppenheim RW, Hester ME, Kaspar BK, Ko CP, Lee KF (2010) Acetylcholine negatively regulates development of the neuromuscular junction through distinct cellular mechanisms. Proceedings of the National Academy of Sciences of the United States of America 107:10702-10707.
Arkell R, Beddington RS (1997) BMP-7 influences pattern and growth of the developing hindbrain of mouse embryos. Development 124:1-12.
Ball RW, Warren-Paquin M, Tsurudome K, Liao EH, Elazzouzi F, Cavanagh C, An BS, Wang TT, White JH, Haghighi AP (2010) Retrograde BMP signaling controls synaptic growth at the NMJ by regulating trio expression in motor neurons. Neuron 66:536-549.
Barone FC, Irving EA, Ray AM, Lee JC, Kassis S, Kumar S, Badger AM, White RF, McVey MJ, Legos JJ, Erhardt JA, Nelson AH, Ohlstein EH, Hunter AJ, Ward K, Smith BR, Adams JL, Parsons AA (2001) SB 239063, a second-generation p38 mitogen-activated protein kinase inhibitor, reduces brain injury and neurological deficits in cerebral focal ischemia. The Journal of pharmacology and experimental therapeutics 296:312-321.
Bensimon G, Lacomblez L, Meininger V (1994) A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. The New England journal of medicine 330:585-591.
Beppu H, Minowa O, Miyazono K, Kawabata M (1997) cDNA cloning and genomic organization of the mouse BMP type II receptor. Biochemical and biophysical research communications 235:499-504.
Borges LS, Yechikhov S, Lee YI, Rudell JB, Friese MB, Burden SJ, Ferns MJ (2008) Identification of a motif in the acetylcholine receptor beta subunit whose phosphorylation regulates rapsyn association and postsynaptic receptor localization. The Journal of neuroscience : the official journal of the Society for Neuroscience 28:11468-11476.
Bragdon B, Moseychuk O, Saldanha S, King D, Julian J, Nohe A (2011) Bone morphogenetic proteins: a critical review. Cellular signalling 23:609-620.
Brandon EP, Lin W, D`Amour KA, Pizzo DP, Dominguez B, Sugiura Y, Thode S, Ko CP, Thal LJ, Gage FH, Lee KF (2003) Aberrant patterning of neuromuscular synapses in choline acetyltransferase-deficient mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 23:539-549.
Caroscio JT, Mulvihill MN, Sterling R, Abrams B (1987) Amyotrophic lateral sclerosis. Its natural history. Neurologic clinics 5:1-8.
Chen X, Weisberg E, Fridmacher V, Watanabe M, Naco G, Whitman M (1997) Smad4 and FAST-1 in the assembly of activin-responsive factor. Nature 389:85-89.
Chiang C, Litingtung Y, Lee E, Young KE, Corden JL, Westphal H, Beachy PA (1996) Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383:407-413.
Choi DW (1987) Ionic dependence of glutamate neurotoxicity. The Journal of neuroscience : the official journal of the Society for Neuroscience 7:369-379.
Ericson J, Morton S, Kawakami A, Roelink H, Jessell TM (1996) Two critical periods of Sonic Hedgehog signaling required for the specification of motor neuron identity. Cell 87:661-673.
Feng Z, Ko CP (2008) Schwann cells promote synaptogenesis at the neuromuscular junction via transforming growth factor-beta1. The Journal of neuroscience : the official journal of the Society for Neuroscience 28:9599-9609.
Ferayorni AJ, Gunville CF, Grow WA (2004) Nicotine decreases agrin signaling and acetylcholine receptor clustering in C2C12 myotube culture. Journal of neurobiology 60:51-60.
Fischer AJ, Schmidt M, Omar G, Reh TA (2004) BMP4 and CNTF are neuroprotective and suppress damage-induced proliferation of Muller glia in the retina. Molecular and cellular neurosciences 27:531-542.
Foletta VC, Lim MA, Soosairajah J, Kelly AP, Stanley EG, Shannon M, He W, Das S, Massague J, Bernard O (2003) Direct signaling by the BMP type II receptor via the cytoskeletal regulator LIMK1. The Journal of cell biology 162:1089-1098.
Friedman B, Scherer SS, Rudge JS, Helgren M, Morrisey D, McClain J, Wang DY, Wiegand SJ, Furth ME, Lindsay RM, et al. (1992) Regulation of ciliary neurotrophic factor expression in myelin-related Schwann cells in vivo. Neuron 9:295-305.
Fuller ML, DeChant AK, Rothstein B, Caprariello A, Wang R, Hall AK, Miller RH (2007) Bone morphogenetic proteins promote gliosis in demyelinating spinal cord lesions. Annals of neurology 62:288-300.
Funakoshi H, Belluardo N, Arenas E, Yamamoto Y, Casabona A, Persson H, Ibanez CF (1995) Muscle-derived neurotrophin-4 as an activity-dependent trophic signal for adult motor neurons. Science 268:1495-1499.
Gautam M, Noakes PG, Moscoso L, Rupp F, Scheller RH, Merlie JP, Sanes JR (1996) Defective neuromuscular synaptogenesis in agrin-deficient mutant mice. Cell 85:525-535.
Gesemann M, Denzer AJ, Ruegg MA (1995) Acetylcholine receptor-aggregating activity of agrin isoforms and mapping of the active site. The Journal of cell biology 128:625-636.
Glass DJ, DeChiara TM, Stitt TN, DiStefano PS, Valenzuela DM, Yancopoulos GD (1996a) The receptor tyrosine kinase MuSK is required for neuromuscular junction formation and is a functional receptor for agrin. Cold Spring Harbor symposia on quantitative biology 61:435-444.
Glass DJ, Bowen DC, Stitt TN, Radziejewski C, Bruno J, Ryan TE, Gies DR, Shah S, Mattsson K, Burden SJ, DiStefano PS, Valenzuela DM, DeChiara TM, Yancopoulos GD (1996b) Agrin acts via a MuSK receptor complex. Cell 85:513-523.
Gould TW, Enomoto H (2009) Neurotrophic modulation of motor neuron development. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry 15:105-116.
Guha U, Gomes WA, Samanta J, Gupta M, Rice FL, Kessler JA (2004) Target-derived BMP signaling limits sensory neuron number and the extent of peripheral innervation in vivo. Development 131:1175-1186.
Hamburger V (1958) Regression versus peripheral control of differentiation in motor hypoplasia. The American journal of anatomy 102:365-409.
Heath PR, Shaw PJ (2002) Update on the glutamatergic neurotransmitter system and the role of excitotoxicity in amyotrophic lateral sclerosis. Muscle & nerve 26:438-458.
Ishii DN (1989) Relationship of insulin-like growth factor II gene expression in muscle to synaptogenesis. Proceedings of the National Academy of Sciences of the United States of America 86:2898-2902.
Jennings CG, Dyer SM, Burden SJ (1993) Muscle-specific trk-related receptor with a kringle domain defines a distinct class of receptor tyrosine kinases. Proceedings of the National Academy of Sciences of the United States of America 90:2895-2899.
Jessell TM (2000) Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nature reviews Genetics 1:20-29.
Jiang Y, Zhang M, Koishi K, McLennan IS (2000a) TGF-beta 2 attenuates the injury-induced death of mature motoneurons. Journal of neuroscience research 62:809-813.
Jiang Y, McLennan IS, Koishi K, Hendry IA (2000b) Transforming growth factor-beta 2 is anterogradely and retrogradely transported in motoneurons and up-regulated after nerve injury. Neuroscience 97:735-742.
Kawabata M, Imamura T, Miyazono K (1998) Signal transduction by bone morphogenetic proteins. Cytokine & growth factor reviews 9:49-61.
Kilpatrick TJ, Soilu-Hanninen M (1999) Molecular mechanisms regulating motor neuron development and degeneration. Molecular neurobiology 19:205-228.
Kim N, Burden SJ (2008) MuSK controls where motor axons grow and form synapses. Nature neuroscience 11:19-27.
Kim N, Stiegler AL, Cameron TO, Hallock PT, Gomez AM, Huang JH, Hubbard SR, Dustin ML, Burden SJ (2008) Lrp4 is a receptor for Agrin and forms a complex with MuSK. Cell 135:334-342.
Kretzschmar M, Massague J (1998) SMADs: mediators and regulators of TGF-beta signaling. Current opinion in genetics & development 8:103-111.
Laake JH, Slyngstad TA, Haug FM, Ottersen OP (1995) Glutamine from glial cells is essential for the maintenance of the nerve terminal pool of glutamate: immunogold evidence from hippocampal slice cultures. Journal of neurochemistry 65:871-881.
Labeur M, Paez-Pereda M, Haedo M, Arzt E, Stalla GK (2010) Pituitary tumors: cell type-specific roles for BMP-4. Molecular and cellular endocrinology 326:85-88.
Lanser ME, Fallon JF (1987) Development of the brachial lateral motor column in the wingless mutant chick embryo: motoneuron survival under varying degrees of peripheral load. The Journal of comparative neurology 261:423-434.
Liem KF, Jr., Tremml G, Jessell TM (1997) A role for the roof plate and its resident TGFbeta-related proteins in neuronal patterning in the dorsal spinal cord. Cell 91:127-138.
Liem KF, Jr., Jessell TM, Briscoe J (2000) Regulation of the neural patterning activity of sonic hedgehog by secreted BMP inhibitors expressed by notochord and somites. Development 127:4855-4866.
Liem KF, Jr., Tremml G, Roelink H, Jessell TM (1995) Dorsal differentiation of neural plate cells induced by BMP-mediated signals from epidermal ectoderm. Cell 82:969-979.
Lin W, Dominguez B, Yang J, Aryal P, Brandon EP, Gage FH, Lee KF (2005) Neurotransmitter acetylcholine negatively regulates neuromuscular synapse formation by a Cdk5-dependent mechanism. Neuron 46:569-579.
Ling KK, Siow NL, Choi RC, Tsim KW (2005) ATP potentiates the formation of AChR aggregate in the co-culture of NG108-15 cells with C2C12 myotubes. FEBS letters 579:2469-2474.
Macpherson PC, Wang X, Goldman D (2011) Myogenin regulates denervation-dependent muscle atrophy in mouse soleus muscle. Journal of cellular biochemistry 112:2149-2159.
Marques G, Bao H, Haerry TE, Shimell MJ, Duchek P, Zhang B, O`Connor MB (2002) The Drosophila BMP type II receptor Wishful Thinking regulates neuromuscular synapse morphology and function. Neuron 33:529-543.
Marti E, Bumcrot DA, Takada R, McMahon AP (1995) Requirement of 19K form of Sonic hedgehog for induction of distinct ventral cell types in CNS explants. Nature 375:322-325.
McCabe BD, Marques G, Haghighi AP, Fetter RD, Crotty ML, Haerry TE, Goodman CS, O`Connor MB (2003) The BMP homolog Gbb provides a retrograde signal that regulates synaptic growth at the Drosophila neuromuscular junction. Neuron 39:241-254.
Misgeld T, Burgess RW, Lewis RM, Cunningham JM, Lichtman JW, Sanes JR (2002) Roles of neurotransmitter in synapse formation: development of neuromuscular junctions lacking choline acetyltransferase. Neuron 36:635-648.
Nilsson EE, Skinner MK (2003) Bone morphogenetic protein-4 acts as an ovarian follicle survival factor and promotes primordial follicle development. Biology of reproduction 69:1265-1272.
Nitkin RM, Smith MA, Magill C, Fallon JR, Yao YM, Wallace BG, McMahan UJ (1987) Identification of agrin, a synaptic organizing protein from Torpedo electric organ. The Journal of cell biology 105:2471-2478.
Nohe A, Keating E, Knaus P, Petersen NO (2004) Signal transduction of bone morphogenetic protein receptors. Cellular signalling 16:291-299.
Okada K, Inoue A, Okada M, Murata Y, Kakuta S, Jigami T, Kubo S, Shiraishi H, Eguchi K, Motomura M, Akiyama T, Iwakura Y, Higuchi O, Yamanashi Y (2006) The muscle protein Dok-7 is essential for neuromuscular synaptogenesis. Science 312:1802-1805.
Oppenheim RW, Prevette D, Haverkamp LJ, Houenou L, Yin QW, McManaman J (1993) Biological studies of a putative avian muscle-derived neurotrophic factor that prevents naturally occurring motoneuron death in vivo. Journal of neurobiology 24:1065-1079.
Oppenheim RW, Wiese S, Prevette D, Armanini M, Wang S, Houenou LJ, Holtmann B, Gotz R, Pennica D, Sendtner M (2001) Cardiotrophin-1, a muscle-derived cytokine, is required for the survival of subpopulations of developing motoneurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 21:1283-1291.
Oza J, Yang J, Chen KY, Liu AY (2008) Changes in the regulation of heat shock gene expression in neuronal cell differentiation. Cell stress & chaperones 13:73-84.
Parikh P, Hao Y, Hosseinkhani M, Patil SB, Huntley GW, Tessier-Lavigne M, Zou H (2011) Regeneration of axons in injured spinal cord by activation of bone morphogenetic protein/Smad1 signaling pathway in adult neurons. Proceedings of the National Academy of Sciences of the United States of America 108:E99-107.
Peng TI, Greenamyre JT (1998) Privileged access to mitochondria of calcium influx through N-methyl-D-aspartate receptors. Molecular pharmacology 53:974-980.
Podkowa M, Zhao X, Chow CW, Coffey ET, Davis RJ, Attisano L (2010) Microtubule stabilization by bone morphogenetic protein receptor-mediated scaffolding of c-Jun N-terminal kinase promotes dendrite formation. Molecular and cellular biology 30:2241-2250.
Qi X, Li TG, Hao J, Hu J, Wang J, Simmons H, Miura S, Mishina Y, Zhao GQ (2004) BMP4 supports self-renewal of embryonic stem cells by inhibiting mitogen-activated protein kinase pathways. Proceedings of the National Academy of Sciences of the United States of America 101:6027-6032.
Reist NE, Werle MJ, McMahan UJ (1992) Agrin released by motor neurons induces the aggregation of acetylcholine receptors at neuromuscular junctions. Neuron 8:865-868.
Riethmacher D, Sonnenberg-Riethmacher E, Brinkmann V, Yamaai T, Lewin GR, Birchmeier C (1997) Severe neuropathies in mice with targeted mutations in the ErbB3 receptor. Nature 389:725-730.
Roelink H, Porter JA, Chiang C, Tanabe Y, Chang DT, Beachy PA, Jessell TM (1995) Floor plate and motor neuron induction by different concentrations of the amino-terminal cleavage product of sonic hedgehog autoproteolysis. Cell 81:445-455.
Rothstein JD, Martin LJ, Kuncl RW (1992) Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. The New England journal of medicine 326:1464-1468.
Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW (1995) Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Annals of neurology 38:73-84.
Rothstein JD, Tsai G, Kuncl RW, Clawson L, Cornblath DR, Drachman DB, Pestronk A, Stauch BL, Coyle JT (1990) Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis. Annals of neurology 28:18-25.
Ruegg MA, Bixby JL (1998) Agrin orchestrates synaptic differentiation at the vertebrate neuromuscular junction. Trends in neurosciences 21:22-27.
Ruegg MA, Tsim KW, Horton SE, Kroger S, Escher G, Gensch EM, McMahan UJ (1992) The agrin gene codes for a family of basal lamina proteins that differ in function and distribution. Neuron 8:691-699.
Ruggiu M, Herbst R, Kim N, Jevsek M, Fak JJ, Mann MA, Fischbach G, Burden SJ, Darnell RB (2009) Rescuing Z+ agrin splicing in Nova null mice restores synapse formation and unmasks a physiologic defect in motor neuron firing. Proceedings of the National Academy of Sciences of the United States of America 106:3513-3518.
Russell FD, Koishi K, Jiang Y, McLennan IS (2000) Anterograde axonal transport of glial cell line-derived neurotrophic factor and its receptors in rat hypoglossal nerve. Neuroscience 97:575-580.
Sabo JK, Aumann TD, Merlo D, Kilpatrick TJ, Cate HS (2011) Remyelination is altered by bone morphogenic protein signaling in demyelinated lesions. The Journal of neuroscience : the official journal of the Society for Neuroscience 31:4504-4510.
Salpeter MM, Cooper DL, Levitt-Gilmour T (1986) Degradation rates of acetylcholine receptors can be modified in the postjunctional plasma membrane of the vertebrate neuromuscular junction. The Journal of cell biology 103:1399-1403.
Schelman WR, Andres RD, Sipe KJ, Kang E, Weyhenmeyer JA (2004a) Glutamate mediates cell death and increases the Bax to Bcl-2 ratio in a differentiated neuronal cell line. Brain research Molecular brain research 128:160-169.
Schelman WR, Andres R, Ferguson P, Orr B, Kang E, Weyhenmeyer JA (2004b) Angiotensin II attenuates NMDA receptor-mediated neuronal cell death and prevents the associated reduction in Bcl-2 expression. Brain research Molecular brain research 128:20-29.
Sendtner M, Kreutzberg GW, Thoenen H (1990) Ciliary neurotrophic factor prevents the degeneration of motor neurons after axotomy. Nature 345:440-441.
Sendtner M, Stockli KA, Thoenen H (1992) Synthesis and localization of ciliary neurotrophic factor in the sciatic nerve of the adult rat after lesion and during regeneration. The Journal of cell biology 118:139-148.
Shi Y, Massague J (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113:685-700.
Sieber C, Kopf J, Hiepen C, Knaus P (2009) Recent advances in BMP receptor signaling. Cytokine & growth factor reviews 20:343-355.
Suzuki A, Nishimatsu S, Shoda A, Takebayashi K, Murakami K, Ueno N (1993) Biochemical properties of amphibian bone morphogenetic protein-4 expressed in CHO cells. The Biochemical journal 291 ( Pt 2):413-417.
Tanaka K, Watase K, Manabe T, Yamada K, Watanabe M, Takahashi K, Iwama H, Nishikawa T, Ichihara N, Kikuchi T, Okuyama S, Kawashima N, Hori S, Takimoto M, Wada K (1997) Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 276:1699-1702.
Valenzuela DM, Stitt TN, DiStefano PS, Rojas E, Mattsson K, Compton DL, Nunez L, Park JS, Stark JL, Gies DR, et al. (1995) Receptor tyrosine kinase specific for the skeletal muscle lineage: expression in embryonic muscle, at the neuromuscular junction, and after injury. Neuron 15:573-584.
Wang PY (2006) Novel survival factors with a gender specific twist for motor neurons: a thesis submitted for the degree of Doctor of Philosophy at the University of Otago, Dunedin, New Zealand: University of Otago.
Wang PY, Koishi K, McLennan IS (2007a) BMP6 is axonally transported by motoneurons and supports their survival in vitro. Molecular and cellular neurosciences 34:653-661.
Wang YL, Wang DZ, Nie X, Lei DL, Liu YP, Zhang YJ, Suwa F, Tamada Y, Fang YR, Jin Y (2007b) The role of bone morphogenetic protein-2 in vivo in regeneration of peripheral nerves. The British journal of oral & maxillofacial surgery 45:197-202.
Weatherbee SD, Anderson KV, Niswander LA (2006) LDL-receptor-related protein 4 is crucial for formation of the neuromuscular junction. Development 133:4993-5000.
Weiss JH (2011) Ca permeable AMPA channels in diseases of the nervous system. Frontiers in molecular neuroscience 4:42.
Whitlon DS, Grover M, Tristano J, Williams T, Coulson MT (2007) Culture conditions determine the prevalence of bipolar and monopolar neurons in cultures of dissociated spiral ganglion. Neuroscience 146:833-840.
Wine-Lee L, Ahn KJ, Richardson RD, Mishina Y, Lyons KM, Crenshaw EB, 3rd (2004) Signaling through BMP type 1 receptors is required for development of interneuron cell types in the dorsal spinal cord. Development 131:5393-5403.
Winnier G, Blessing M, Labosky PA, Hogan BL (1995) Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse. Genes & development 9:2105-2116.
Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, Hewick RM, Wang EA (1988) Novel regulators of bone formation: molecular clones and activities. Science 242:1528-1534.
Wrana JL, Attisano L, Wieser R, Ventura F, Massague J (1994) Mechanism of activation of the TGF-beta receptor. Nature 370:341-347.
Wu H, Xiong WC, Mei L (2010) To build a synapse: signaling pathways in neuromuscular junction assembly. Development 137:1017-1033.
Zhang B, Luo S, Wang Q, Suzuki T, Xiong WC, Mei L (2008) LRP4 serves as a coreceptor of agrin. Neuron 60:285-297.
Zhu JJ, Qin Y, Zhao M, Van Aelst L, Malinow R (2002) Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell 110:443-455.		zh_TW