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本研究では、脳の形成と機能に必須な分泌タンパク質リーリンの N-t 切断に着目し、
脳におけるリーリンN-t切断酵素の同定、およびN-t切断によるリーリンの機能的制御 の生理的意義の解明を目指した。そして、私は以下の知見を得た。
1. ADAMTS-3は大脳皮質、海馬、小脳プルキンエ細胞に発現する。
2. Adamts3–/–マウスは骨形成異常を示し、その多くが生後すぐに死亡する。
3. N-t切断はリーリンの不活化機構である。
4. ADAMTS-3が、大脳皮質と海馬でリーリンを切断して不活化する酵素である。
5. N-t切断によるリーリンの機能制御は大脳皮質神経細胞形態を制御する。
6. リーリン－Dab1シグナルは、OPCsの増殖を抑制する。
7. リーリン－Dab1シグナルは、OPCsの移動に対して忌避的に働く。
8. N-t 切断によるリーリンの機能制御は OPCs の増殖および配置の制御に寄与する。
本研究より、リーリンの機能制御機構とその生理的意義、そしてOPCsの増殖と配置 を制御するというリーリンの新規機能が明らかとなった。以上は、N-t切断によるリー リンの機能制御機構が、脳の正常な構築に重要な役割を担っていることを示唆する重要 な知見であると考えている。今後さらに、リーリンの機能制御機構が脳機能等に及ぼす 影響が明らかになれば、リーリン機能低下が関与する神経疾患の発症・増悪化のメカニ ズムの解明と治療に貢献すると期待される。
63 引用文献
Apte SS (2009) A disintegrin-like and metalloprotease (reprolysin-type) with thrombospondin type 1 motif (ADAMTS) superfamily: functions and mechanisms. J Biol Chem 284:
31493–31497.
Arnaud L, Ballif BA, Förster E, Cooper JA (2003) Fyn tyrosine kinase is a critical regulator of Disabled-1 during brain development. Curr Biol 13(1), 9–17.
Bradley A et al. (2012) The mammalian gene function resource: the international knockout mouse consortium. Mamm Genome 23:580–586.
Bergles DE, Richardson WD (2015) Oligodendrocyte development and plasticity. Cold Spring Harb Perspect Biol 8:a020453.
Beffert U, Morfini G, Bock HH, Reyna H, Brady ST, Herz J (2002) Reelin-mediated signaling locally regulates protein kinase B/Akt and glycogen synthase kinase 3β. J Biol Chem 277(51), 49958–49964.
Beffert U, Weeber EJ, Durudas A, Qiu S, Masiulis, I, Sweatt JD, Li W, Adelmann G, Frotscher M, Hammer RE, Herz, J. (2005) Modulation of synaptic plasticity and memory by Reelin involves differential splicing of the lipoprotein receptor Apoer2. Neuron, 47(4), 567–579.
Bekhouche M, Leduc C, Dupont L, Janssen L, Delolme F, Vadon-Le Goff S, Smargiasso N, Baiwir D, Mazzucchelli G, Zanella-Cleon I, Dubail J, De Pauw E, Nusgens B, Hulmes DJ, Moali C, Colige A (2016) Determination of the substrate repertoire of ADAMTS2, 3, and 14 significantly broadens their functions and identifies extracellular matrix organization and TGF-beta signaling as primary targets. FASEB J 30:1741–56.
Birey F, Kokkosis AG, Aguirre A (2017) Oligodendroglia-lineage cells in brain plasticity, homeostasis and psychiatric disorders. Curr Opin Neurobiol 47:93–103.
Bock HH, Herz J (2003) Reelin Activates Src Family Tyrosine Kinases in Neurons. Curr Biol 13(2), 18–26.
Botella-López A, Burgaya F, Gavín R, García-Ayllón MS, Gómez-Tortosa E, Peña-Casanova J, Ureña JM, Río JAD, Blesa R, Soriano E, Sáez-Valero, J (2006) Reelin expression and glycosylation patterns are altered in Alzheimer’s disease. Proc Natl Acad Sci U S A 103(14), 5573–5578.
64
Bradley A, Anastassiadis K, Ayadi A, Battey JF, Bell C, Birling MC, Bottomley J, Brown SD, Burger A, Bult CJ, et al. (2012) The mammalian gene function resource: the International Knockout Mouse Consortium. Mamm Genome 23:580–586.
Brion JP, Smith C, Couck AM, Gallo JM, Anderton BH (1993) Developmental changes in tau phosphorylation: fetal tau is transiently phosphorylated in a manner similar to paired helical filament-tau characteristic of Alzheimer’s disease. J Neurochem 61(6), 2071–
80.
Bui HM, Enis, D, Robciuc MR, Nurmi HJ, Cohen J, Chen M, Yang Y, Dhillon V, Johnson K, Zhang H, Kirkpatrick R, Traxler E, Anisimov A, Alitalo K, Kahn ML (2016) Proteolytic activation defines distinct lymphagiogenic mechanisms for VEGFC and VEGFD. J Clin Invest 126:2167–2180.
Calver AR, Hall AC, Yu W-P, Walsh FS, Heath JK, Betsholtz C, Richardson WD (1998) Oligodendrocyte population dynamics and the role of PDGF in vivo. Neuron 20:869–
882.
Caruncho HJ, Brymer K, Romay-Tallón R, Mitchell MA, Rivera-Baltanás T, Botterill J, Olivares JM, Kalynchuk LE (2016) Reelin-related disturbances in depression: Implications for translational studies. Front Cell Neurosci 10:48.
Chameau P, Inta D, Vitalis T, Monyer H, Wadman WJ, van Hooft JA (2009) The N-terminal region of Reelin regulates postnatal dendritic maturation of cortical pyramidal neurons. Proc Natl Acad Sci U S A 106:7227–7232.
Chen Y, Beffert U, Ertunc M, Tang T, Kavalali ET, Bezprozvanny I, Herz J (2005) Reelin modulates NMDA receptor activity in cortical neurons. J Neurosci 25(36), 8209–8216.
Chen X-S, Zhang Y-H, Cai Q-Y, Yao Z-X (2012) ID2: A negative transcription factor regulating oligodendroglia differentiation. J Neurosci Res 90:925–932.
Chen X, Duan H, Xiao L, Gan J (2018) Genetic and epigenetic alterations underlie oligodendroglia susceptibility and white matter etiology in psychiatric disorders. Front Genet 9:565.
Chin J, Massaro CM, Palop JJ, Thwin MT, Yu G, Bien-Ly N, Bender A, Mucke L (2007) Reelin depletion in the entorhinal cortex of human amyloid precursor protein transgenic mice and humans with Alzheimer’s disease. J Neurosci 27(11), 2727–2733.
Choe Y, Huynh T, Pleasure SJ (2014) Migration of oligodendrocyte progenitor cells is controlled by transforming growth factor β family proteins during corticogenesis. J Neurosci 34:14973–14983.
65
Cosgaya JM, Chan JR, Shooter EM (2002) The neurotrophin receptor p75NTR as a positive modulator of myelination. Science 298:1245–1248.
D'Arcangelo G, Miao GG, Chen SC, Soares HD, Morgan JI, Curran T (1995) A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature 374:719–723.
D’Arcangelo G, Nakajima K, Miyata T, Ogawa M, Mikoshiba K, Curran T (1997) Reelin is a secreted glycoprotein recognized by the CR-50 monoclonal antibody. J Neurosci 17(1), 23–31.
D'Arcangelo G, Homayouni R, Keshvara L, Rice DS, Sheldon M, Curran T (1999) Reelin is a ligand for lipoprotein receptors. Neuron 24:471–479.
Di Donato V, De Santis F, Albadri S, Auer TO, Duroure K, Charpentier M, Concordet J-P, Gebhardt C, Del Bene F (2018) An attractive reelin gradient establishes synaptic lamination in the vertebrate visual system. Neuron 97:1049-1062.
Durakoglugil MS, Chen Y, White CL, Kavalali ET, Herz J (2009) Reelin signaling antagonizes beta-amyloid at the synapse. Proc Natl Acad Sci U S A 106(37), 15938–43.
Dubail J, Apte SS (2015) Insights on ADAMTS proteases and ADAMTS-like proteins from mammalian genetics. Matrix Biol 44–46:24-37.
Emery B, Lu QR (2015) Transcriptional and epigenetic regulation of oligodendrocyte development and myelination in the central nervous system. Cold Spring Harb Perspect Biol 7:a020461.
Ernfors P, Wetmore C, Olson L, Persson H (1990) Identification of cells in rat brain and peripheral tissues expressing mRNA for members of the nerve growth factor family. Neuron 5:511–526.
Feng L, Allen NS, Simo S, Cooper JA (2007) Cullin 5 regulates Dab1 protein levels and neuron positioning during cortical development. Genes Dev 21:2717–2730.
Fernandes RJ, Hirohata S, Engle JM, Colige A, Cohn DH, Eyre DR, Apte SS (2001) Procollagen II amino propeptide processing by ADAMTS-3. Insights on dermatosparaxis. J Biol Chem 276:31502–31509.
Fields RD (2008) White matter in learning, cognition and psychiatric disorders. Trends Neurosci 31:361–370.
Folsom TD, Fatemi SH (2013) The involvement of Reelin in neurodevelopmental disorders.
Neuropharmacology 68:122–135.
Fruttiger M, Karlsson L, Hall AC, Abramsson A, Calver AR, Boström H, Willetts K, Bertold CH, Heath JK, Betsholtz C, Richardson WD (1999) Defective oligodendrocyte
66
development and severe hypomyelination in PDGF-A knockout mice. Development 126:457–467.
Groc L, Choquet D, Stephenson FA, Verrier D, Manzoni OJ, Chavis P (2007) NMDA receptor surface trafficking and synaptic subunit composition are developmentally regulated by the extracellular matrix protein Reelin. J Neurosci 27(38), 10165–10175.
Guidotti A, Auta J, Davis JM, Gerevini VD, Dwivedi Y, Grayson DR, Impagnatiello F, Pandey G, Pesold C, Sharma R, Uzunov D, Costa E. (2000) Decrease in Reelin and Glutamic Acid Decarboxylase 67 (GAD 67) Expression in Schizophrenia and Bipolar Disorder. Arch Gen Psychiatry 57(11), 1061–1069.
Hack I, Hellwig S, Junghans D, Brunne B, Bock HH, Zhao S, Frotscher M (2007) Divergent roles of ApoER2 and VLDLR in the migration of cortical neurons. Development 134:3883–
3891.
Herz J, Chen Y (2006) Reelin, lipoprotein receptors and synaptic plasticity. Nat Rev Neurosci 7:850–859.
Hiesberger T, Trommsdorff M, Howell BW, Goffinet A, Mumby MC, Cooper JA, Herz J (1999) Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation. Neuron 24:481–489.
Hirota Y, Nakajima K (2017) Control of neuronal migration and aggregation by Reelin signaling in the developing cerebral cortex. Front Cell Dev Biol 5:40.
Hisanaga A, Morishita S, Suzuki K, Sasaki K, Koie M, Kohno T, Hattori M (2012) A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4) cleaves Reelin in an isoform-dependent manner. FEBS Lett 586:3349–3353.
Howell BW, Hawkes R, Soriano P, Cooper JA (1997) Neuronal position in the developing brain is regulated by mouse disabled-1. Nature 389:733–737.
Howell BW, Herrick TM, Cooper JA (1999) Reelin-induced tryosine phosphorylation of disabled 1 during neuronal positioning. Genes Dev 13:643–648.
Impagnatiello F, Guidotti AR, Pesold C, Dwivedi Y, Caruncho H, Pisu MG, Uzynov DP, Smalheiser NR, Davis JM, Pandey GN, Pappas GD, Tueting P, Sharma RP, Costa E (1998) A decrease of reelin expression as a putative vulnerability factor in schizophrenia. Proc Natl Acad Sci U S A 95(26), 15718–23.
Ishii K, Kubo K, Nakajima K (2016) Reelin and neuropsychiatric disorders. Front Cell Neurosci 10:229.
67
Iwasato T, Nomura R, Ando R, Ikeda T, Tanaka M, Itohara S (2004) Dorsal telencephalon-specific expression of Cre recombinase in PAC transgenic mice. Genesis 38:130–138.
Janssen L, Dupont L, Bekhouche M, Noel A, Leduc C, Voz M, Peers B, Cataldo D, Apte SS, Dubail J, Colige A (2016) ADAMTS3 activity is mandatory for embryonic lymphangiogenesis and regulates placental angiogenesis. Angiogenesis 19:53–65.
Jossin Y, Ignatova N, Hiesberger T, Herz J, Lambert de Rouvroit C, Goffinet AM (2004) The Central Fragment of Reelin, Generated by Proteolytic Processing In Vivo, Is Critical to Its Function during Cortical Plate Development. J Neurosci 24(2), 514–521.
Jossin Y, Goffinet AM (2007) Reelin signals through phosphatidylinositol 3-kinase and Akt to control cortical development and through mTor to regulate dendritic growth. Mol Cell Biol 27:7113–7124.
Jossin Y, Gui L, Goffinet AM (2007) Processing of Reelin by embryonic neurons is important for function in tissue but not in dissociated cultured neurons. J Neurosci 27:4243–4252.
Kessaris N, Fogarty M, Iannarelli P, Grist M, Wegner M, Richardson WD (2006) Competing waves of oligodendrocytes in the forebrain and postnatal elimination of an embryonic lineage. Nat Neurosci 9:173–179.
Kocherhans S, Madhusudan A, Doehner J, Breu KS, Nitsch RM, Fritschy J, Knuesel I (2010) Reduced Reelin Expression Accelerates Amyloid Plaque Formation and Tau Pathology in Transgenic Alzheimer’ s Disease Mice. J Neurosci 30(27), 9228–9240.
Kohno S, Kohno T, Nakano Y, Suzuki K, Ishii M, Tagami H, Baba A, Hattori M (2009) Mechanism and significance of specific proteolytic cleavage of Reelin. Biochem Biophys Res Commun 380:93–97.
Kohno T, Honda T, Kubo K, Nakano Y, Tsuchiya A, Murakami T, Banno H, Nakajima K, Hattori M (2015) Importance of reelin C-terminal region in the development and maintenance of the postnatal cerebral cortex and its regulation by specific proteolysis. J Neurosci 35:4776–4787.
Koie M, Okumura K, Hisanaga A, Kamei T, Sasaki K, Deng M, Baba A, Kohno T, Hattori M (2014) Cleavage within Reelin repeat 3 regulates the duration and range of the signaling activity of Reelin protein. J Biol Chem 289:12922–12930.
Krstic D, Rodriguez M, Knuesel I (2012) Regulated proteolytic processing of Reelin through interplay of tissue plasminogen activator (tPA), ADAMTS-4, ADAMTS-5, and their modulators. PLoS One 7:e47793.
68
Krstic D, Pfister S, Notter T, Knuesel I (2013) Decisive role of Reelin signaling during early stages of Alzheimer's disease. Neuroscience 246:108–116.
Kumar S, Kahn MA, Dinh L, de Vellis J (1998) NT-3-mediated TrkC receptor activation promotes proliferation and cell survival of rodent progenitor oligodendrocyte cells in vitro and in vivo. J Neurosci Res 54:754–765.
Kupferman JV, Basu J, Russo MJ, Guevarra J, Cheung SK, Siegelbaum SA (2014) Reelin signaling specifies the molecular identity of the pyramidal neuron distal dendritic compartment. Cell 158:1335–1347.
Kwon OY, Hwang K, Kim J, Kim K, Kwon IC, Song HK, Jeon H (2010) Dab1 binds to Fe65 and diminishes the effect of Fe65 or LRP1 on APP processing. J Cell Biochem 111, 508–
19.
Lambert de Rouvroit C, de Bergeyck V, Cortvrindt C, Bar I, Eeckhout Y, Goffinet AM (1999) Reelin, the extracellular matrix protein deficient in reeler mutant mice, is processed by a metalloproteinase. Exp Neurol 156:214–217.
Lane-Donovan C, Philips GT, Wasser CR, Durakoglugil MS, Masiulis I, Upadhaya A, Pohlkamp T, Coskun C, Kotti T, Steller L, Hammer RE, Frotscher M, Bock HH, Herz J (2015) Reelin protects against amyloid beta toxicity in vivo. Sci Signal 8:ra67.
Le Goff C, Somerville RP, Kesteloot F, Powell K, Birk DE, Colige AC, Apte SS (2006) Regulation of procollagen amino-propeptide processing during mouse embryogenesis by specialization of homologous ADAMTS proteases: insights on collagen biosynthesis and dermatosparaxis. Development 133:1587–1596.
Li S, Darwin JP, Helminen H, Lui H, Khillan JS (1995) Transgenic mice with targeted for collagen 11 develop a skeleton with membranous and periosteal bone but no endochondral bone.
Genes Dev 9, 2821–2830.
Lorenzetto E, Panteri R, Marino R, Keller F, Buffelli M (2008) Impaired nerve regeneration in reeler mice after peripheral nerve injury. Eur J Neurosci 27:12–19.
Lussier AL, Lebedeva K, Fenton EY, Guskjolen A, Caruncho HJ, Kalynchuk LE (2013) The progressive development of depression-like behavior in corticosterone-treated rats is paralleled by slowed granule cell maturation and decreased reelin expression in the adult dentate gyrus. Neuropharmacology, 71, 174–183.
Maisonpierre PC, Belluscio L, Friedman B, Alderson RF, Wiegand SJ, Furth ME, Lindsay RM, Yancopoulos GD (1990) NT-3, BDNF, and NGF in the developing rat nervous system:
Parallel as well as reciprocal patterns of expression. Neuron 5:501–509.
69
Matsuki T, Matthews RT, Cooper JA, van der Brug MP, Cookson MR, Hardy JA, Olson EC, Howell BW (2010) Reelin and Stk25 have opposing roles in neuronal polarization and dendritic Golgi deployment. Cell 143:826–836.
Mawal-Dewan M, Henley J, Van De Voorde A, Trojanowski JQ, Lee VMY (1994) The phosphorylation state of tau in the developing rat brain is regulated by phosphoprotein phosphatases. J Biol Chem 269(49), 30981–30987.
Meseke M, Neumüller F, Brunne B, Li X, Anstötz M, Pohlkamp T, Rogalla MM, Herz J, Rune GM, Bender RA (2018) Distal dendritic enrichment of HCN1 channels in hippocampal CA1 is promoted by estrogen, but does not require Reelin. eNeuro 5:ENEURO.0258-18.2018.
Mikoshiba K, Takamatsu K, Tsukada Y (1985) Altered myelinated fiber trajectory at various postnatal days in the cerebral cortex of reeler mice by immunohistochemical stain with MBP antiserum. Dev Neurosci 7:199–205.
Mitew S, Hay CM, Peckham H, Xiao J, Koenning M, Emery B (2014) Mechanisms regulating the development of oligodendrocytes and central nervous system myelin. Neuroscience 276:29–47.
Miyamoto Y, Yamauchi J, Tanoue A (2008) Cdk5 phosphorylation of WAVE2 regulates oligodendrocyte precursor cell migration through nonreceptor tyrosine kinase Fyn. J Neurosci 28:8326–8337.
Niu S, Renfro A, Quattrocchi CC, Sheldon M, D'Arcangelo G (2004) Reelin promotes hippocampal dendrite development through the VLDLR/ApoER2-Dab1 pathway.
Neuron 41:71–84.
Niu S, Yabut O, D’Arcangelo G (2008) The Reelin Signaling Pathway Promotes Dendritic Spine Development in Hippocampal Neurons. J Neurosci 28(41), 10339–10348.
O'Dell RS, Cameron DA, Zipfel WR, Olson EC (2015) Reelin prevents apical neurite retraction during terminal translocation and dendrite initiation. J Neurosci 35:10659–10674.
Ogino H, Hisanaga A, Kohno T, Kondo Y, Okumura K, Kamei T, Sato T, Asahara H, Tsuiji H, Fukata M, Hattori M (2017) Secreted metalloproteinase ADAMTS-3 inactivates Reelin.
J Neurosci 37:3181–3191.
Ohkubo N, Lee YD, Morishima A, Terashima T, Kikkawa S, Tohyama M, Sakanaka M, Tanaka J, Maeda N, Vitek MP, Mitsuda N (2003) Apolipoprotein E and Reelin ligands modulate tau phosphorylation through an Apolipoprotein E receptor / disabled-1 / glycogen synthase kinase-3β cascade. FASEB J 17:295–297.
70
Panteri R, Mey J, Zhelyaznik N, D’Altocolle A, Del Fà A, Gangitano C, Marino R, Lorenzetto E, Buffelli M, Keller F (2006) Reelin is transiently expressed in the peripheral nerve during development and is upregulated following nerve crush. Mol Cell Neurosci 32:133–142.
Pasten C, Cerda J, Jausoro I, Court FA, Cáceres A, Marzolo M-P (2015) ApoER2 and Reelin are expressed in regenerating peripheral nerve and regulate Schwann cell migration by activating the Rac1 GEF protein, Tiam1. Mol Cell Neurosci 69:1–11.
Pramatarova A, Chen K, Howell, BW (2008) A genetic interaction between the APP and Dab1 genes influences brain development. Mol. Cell. Neurosci 37, 178–186.
Pujadas L, Rossi D, Andres R, Teixeira CM, Serra-Vidal B, Parcerisas A, Maldonado R, Giralt E, Carulla N, Soriano E (2014) Reelin delays amyloid-beta fibril formation and rescues cognitive deficits in a model of Alzheimer's disease. Nat Comm 5:3443.
Rice HC, Young-pearse TL, Selkoe DJ (2014) Systematic evaluation of candidate ligands regulating ectodomain shedding of Amyloid Precursor Protein. Biochemistry 52(19), 1–24.
Rogers JT, Rusiana I, Trotter J, Zhao L, Donaldson E, Pak DTS, Babus LW, Peters M, Banko JL, Chavis P, Rebeck GW, Hoe HS, Weeber EJ (2011) Reelin supplementation enhances cognitive ability, synaptic plasticity, and dendritic spine density. Learn Mem 18(9), 558–64.
Rogers JT, Zhao L, Trotter JH, Rusiana I, Peters MM, Li Q, Donaldson E, Banko JL, Keenoy KE, Rebeck GW, Hoe HS, D'Arcangelo G, Weeber EJ (2013) Reelin supplementation recovers sensorimotor gating, synaptic plasticity and associative learning deficits in the heterozygous reeler mouse. J Pychopharmacol 27:386–395.
Sáez-Valero J, Costell M, Sjogren M, Andreasen N, Blennow K, Luque JM (2003) Altered levels of cerebrospinal fluid reelin in frontotemporal dementia and Alzheimer’s disease. J Neurosci Res 72(1), 132–136.
Sakai K, Shoji H, Kohno T, Miyakawa T, Hattori M (2016) Mice that lack the C-terminal region of Reelin exhibit behavioral abnormalities related to neuropsychiatric disorders. Sci Rep 6:28636.
Samanta J, Kessler JA (2004) Interactions between ID and OLIG proteins mediate the inhibitory effects of BMP4 on oligodendroglial differentiation. Development 131:4131–4142.
Sekine K, Kubo K, Nakajima K (2014) How does Reelin control neuronal migration and layer formation in the developing mammalian neocortex? Neurosci Res 86:50–58.
71
Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, et al. (2011) A conditional knockout resource for the genome-wide study of mouse gene function. Nature 474:337–342.
Siebert JR, Osterhout DJ (2011) Oligodendroglial cells express and secrete reelin. Anat Rec 294:759–763.
Stranahan AM, Erion JR, Wosiski-Kuhn M (2013) Reelin signaling in development, maintenance, and plasticity of neural networks. Ageing Res Rev 12:815–822.
Strasser V, Fasching D, Hauser C, Mater H, Bock HH, Hiesberger T, Herz J, Weeber EJ, Sweatt JD, Pramatarova A, Howell B, SchneiderWJ, Nimpf J (2004) Receptor Clustering is involved in Reelin signaling. Mol Cell Biol 24: 1378-1386.
Tan S-S, Kalloniatis M, Truong H-T, Binder MD, Cate HS, Kilpatrick TJ, Hammond VE (2009) Oligodendrocyte positioning in cerebral cortex is independent of projection neuron layering. Glia 57:1024–1030.
Talebian S, Gharesouran J, Ghafouri-Fard S, Esfahani BS, Arsang-Jang S, Omrani MD, Taheri M, Rezazadeh M (2019) Assessment of expression of RELN signaling pathway in multiple sclerosis patients. Immunobiology 224:402–407.
Teixeira CM, Martin ED, Sahun I, Masachs N, Pujadas L, Corvelo A, Bosch C, Rossi D, Martinez A, Maldonado R, Dierssen M, Soriano E (2011) Overexpression of Reelin prevents the manifestation of behavioral phenotypes related to schizophrenia and bipolar disorder.
Neuropsychopharmacology 36:2395–2405.
Tinnes S, Ringwald J, Haas CA (2013) TIMP-1 inhibits the proteolytic processing of Reelin in experimental epilepsy. FASEB J 27:2542–2552.
Uchida T, Baba A, Perez-Martinez FJ, Hibi T, Miyata T, Luque JM, Nakajima K, Hattori M (2009) Downregulation of functional Reelin receptors in projection neurons implies that primary Reelin action occurs at early/premigratory stages. J Neurosci 29:10653–10622.
Utsunomiya-Tate N, Kubo K, Tate S, Kainosho M, Katayama E, Nakajima K, Mikoshiba K (2000) Reelin molecules assemble together to form a large protein complex, which is inhibitited by the function-blocking CR-50 antibody. Proc Natl Acad Sci U S A 97:9729-2734.
Wang S, Sdrulla A, Johnson JE, Yokota Y, Barres BA (2001) A role for the helix-loop-helix protein Id2 in the control of oligodendrocyte development. Neuron 29:603–614.
Wasser CR, Herz J (2017) Reelin: Neurodevelopmental architect and homeostatic regulator of excitatory synapses. J Biol Chem 292:1330–1338.
72
Weeber EJ, Beffert U, Jones C, Christian JM, Förster E, David Sweatt J, Herz J (2002) Reelin and apoE receptors cooperate to enhance hippocampal synaptic plasticity and learning. J Biol Chem 277(42), 39944–39952.
Winkler CC, Yabut OR, Fregoso SP, Gomez HG, Dwyer BE, Pleasure SJ, Franco SJ (2018) The dorsal wave of neocortical oligodendrogenesis begins embryonically and requires multiple sources of Sonic hedgehog. J Neurosci 38:5237–5250.
Wolswijk G, Noble M (1992) Cooperation between PDGF and FGF converts slowly dividing O-2Aadult progenitor cells to rapidly dividing cells with characteristics of O-2Aperinatal progenitor cells. J Cell Biol 118:889–900.
Yasui N, Nogi T, Kitao T, Nakano Y, Hattori M, Takagi J (2007) Structure of a receptor-binding fragment of reelin and mutational analysis reveal a recognition mechanism similar to endocytic receptors. Proc Natl Acad Sci U S A 104(24), 9988–93.
Yamakage Y, Tsuiji H, Kohno T, Ogino H, Saito T, Saido TC, Hattori M (2019a) Reducing ADAMTS-3 inhibits amyloid β deposition in App knock-in mouse. Biol Pharm Bull 42, 354-356
Yamakage Y, Kato M, Hongo A, Tsuiji H, Kohno T, Ogino H, Ishii K, Ishizuka T, Kamei T, Tsuiji H, Miyamoto T, Oishi H, Kohno T, Hattori M (2019b) A disintegrin and metalloproteinase with thrombospondin motifs 2 cleaves and inactivates Reelin in the postnatal cerebral cortex and hippocampus, but not in the cerebellum. Mol Cell Neurosci 100, 103401
Yu Y, Run X, Liang Z, Li Y, Liu F, Liu Y, Iqbal K, Grundke-Iqubal I, Gong CX (2009) Developmental regulation of tau phosphorylation, tau kinases, and tau phosphatases. J Neurochem 108(6), 1480–1494.
Zhang JH, Zhao YF, He XX, Zhao Y, He Z, Zhang L, Huang Y, Wang Y, Hu L, Liu L, Yu H, Xu J, Lai M, Zhao D, Cui L, Guo W, Xiong W, Ding Y, Zhu XJ (2018) DCC-Mediated Dab1 phosphorylation participates in the multipolar-to-bipolar transition of migrating neurons. Cell Rep 22, 3598–3611.
73 謝辞
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本論文の作成にあたり、多大な御指導と有益なる御助言を賜りました名古屋市立大学 大学院薬学研究科、青山峰芳教授、田中正彦准教授、ならびに名古屋市立大学 大学院 医学研究科、齊藤貴志教授に深く感謝申し上げます。
本研究を遂行するにあたり、いつも丁寧に、熱心に御指導して頂きました名古屋市立 大学 大学院薬学研究科、河野孝夫講師に心より御礼申し上げます。
本研究を遂行するにあたり、的確な御助言を賜りました名古屋市立大学 大学院薬学研 究科、築地仁美講師に厚く御礼申し上げます。
本研究を遂行するにあたり、終始温かな御指導とご協力を賜りました慶應義塾大学 医 学部、仲嶋一範教授に心より御礼申し上げます。
大脳皮質神経細胞の培養上清よりプロテアーゼを同定するにあたって、質量分析を行 って頂きました自然科学研究機構生理学研究所 細胞器官研究系生体膜研究部門、深田 正紀教授に厚く御礼申し上げます。
本研究を遂行するにあたり、Vldlr–/–マウスの解析で多大なる御尽力と御助言を頂きま した慶應義塾大学 医学部、廣田ゆき専任講師に心より感謝致します。
本研究を遂行するにあたり、RelnDV/DVマウスを作製していただきました名古屋市立大 学 大学院医学研究科、大石久史教授に深謝致します。
マウスの骨標本を作製して頂きました、東京医科歯科大学 医学部、浅原弘嗣教授、佐 藤天平特任助教（現・理化学研究所）に深く御礼申し上げます。