研究成果報告書

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1 !"#$%& '()*+,-./0'()*+1,23)* :;<%=>?% )*DE<F??&GF?%% HI:;<F%F=??FJ )*HIK0LM3N-OPQRSTUVWXYZ[\]^Q_`a NNNNNNNNNNNNNNNNNNNN )*HIK0bM3NThe significance of adult neurogenesis )*cde NfgNhijN0KAGEYAMA RYOICHIRO3 klm(nopqr)*sntu ü)*e:;<j?ff=>v&!"#$%$&#'()* QRASTU"6789:;<=>AVWXHYZ[\]^._`AabHcdeJfghi jklmjnreopgqrcsnretfguv_`cwretfg^_`xywz{jz CEwR }~ ÄÅÇÉ.ÑÖJÜ^_`.yWxádàHYâäDCJ"6789:;< =>}JfghijklJ^_`JÜ^_`cTàHãfåEç;éèêz{HZ[\]å_ `EëíIUì0îïñAóòdcxBCDEîàHY +,"-./01ô345To understand the significance of adult neurogenesis, we genetically ablated newly born neurons in the adult mouse brain. Mutant mice showed defects in predator odor avoidance. Furthermore, mutant males displayed deficits in male-male aggression and sexual behaviors toward females, while mutant females displayed deficits in fertility and nurturing. These results suggest that adult neurogenesis plays an essential role in predator avoidance and gender-specific responses that are olfactory-dependent and innately programmed. öõúùû üüüüüüüüüüüüüüüüüüüüüüüüüüüüüüü1 û 5 4 ß ß ü # % 15,400,000 4,620,000 20,020,000 # Æ % 10,500,000 3,150,000 13,650,000 # ÆÆ% 10,500,000 3,150,000 13,650,000 Øü 36,400,000 10,920,000 47,320,000 +, ±5 >> µ +ß. Ä 57 µä µ ª:º: 5"67J89:;<=>J æ øj J ƒjz Æ +,.Àà ü"67.89:;<} EÕ>XîT x J Œ œ c X U 7. ä Ö (subventricular zone of lateral ventricle, LV- SVZ) o ƒ. ø Ö (subgranular zone of dentate gyrus, DG-SGZ). #Dÿ 89:;<=>xádGYTŸ{. E "6 æ øx]*xj fi >. Jfl Ÿ89:;<A> ÅFY 7.ä Ö > {H ø}j E ÂXJZ.89:;< ÊG ømáë 6 øe ÈFGY ÍJ ƒ. øö > {H ø} ƒ.89:;< ÊG øe ÈF GYd{C.89:;<}JœÎÏÌEt FGÓÔJ ÒJµÚEÛíGdcxÙı z{utgxjˆ.ì0^ä?@e TU } ídàutîdàhyd.+,. {}J"67.89:;<=>A XH IH FG ˇî!"x#DàHHI ÊGYŒ $JX %&'m()*+,e G æ ø.-./0x1 C{Uë HxJ/0x23 ÊGdcc89:; <EtFG45S.HIJ678-.9:

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3 WFGcfghEtFGløxOÈFGd cxbcdcîàhy 89:;<=>AVWXHwRPQR}~ ÉxÑÖXJ H~ AÙ ëÿjı ÇXmF îàutgdcxídàh1 x4yzcej89:;<=>avwxhw RPQR}ÚAÅÇXU Jˆ åem UA_íŸJÚA _XH ÊàHY =>Ú.. E}Ü x câêô z {ŸJ=>Ú. câê}>z î W âk EN XH1 $4Yd{C.8-DCJ" 6789:;<=>AVWFGc~.Ù mm UîÊJwREFåî_`E ëîfixqc{gdcxbcdcîàhy #5fgh ì ì }n«c EJÄ<C ;:Åh ë âçó }n«#x ÙXHY Ä<C;:ÅPQR}n«xÊàU fg heœÿeòc}xîtxj89:;<= >AVWXH Ÿ ã çã PQR}n«xÊGc fgheœÿg òeîàhy HU;S<E\]XH^EFå_` üøejhu;s<e àu áz{g > î^efå_`e TU9wXHY ŸJ nrpqr.uv_`e TUabHY± >ªnRPQRAÆ fiôfl XJ.îTnRAˆ. :GE {UmGcJ nrpqr} ÆEtXUuv_`AÙ FdcxrC{UTGYcdexJ89: ;<=>AVWXHPQR }Jd. ò î ÆEtFGuv_`} câêqc {îdàhyøej±>ªwrpqret FGnRPQR.öÁ_`AabHcdeJ 89:;<=>AVWXHPQR}wRP QREtXUöÁ_`AÙzŸJwRPQ REËÈ1plug4} câêùûz{îdà HYd{C.8-DCJ"6789:;< =>AVWFGcuv_`möÁ_`îÊJ nrefåî_`efixqc{gdcx BCDcîàHY x589:;<=>avwxhwrpq R} J~ " Í. ñ xî X ÑÖ XH 1Ï4YzCEJ~ x"íxu ÅÇEÌ GÉxqrXH1Ó4Y ü89:;<=>avwxhwrpqra 9wXHcdeJplug x ëe J H plug xô ëhpqr.òòjúa#ûeå Ç ëhpqr.ñ ±>ªPQR.o ˆq ÊàH1 x4yfîíòj $589:;<=>AVWXHÜ PQ RDCÇ {HÚ.. E} câêü xqc{îdàhy üâä.8-dcj" 6789:;<=> }JfghEtFGløJ^_`mM U îêjãfåeç;éèêz{h Tlø Eµ ÊGdcxíDàHY ' î ˇ!3" 1+,#ˇÆJ+, óæ$ %&+,Æ E}Ö%4 '()!3*1 #'+4 (1) Horn, S., Kobberup, S., Jørgensen. M.C., Kalisz, M., Klein, T., Kageyama, R., Gegg, M., Lickert, H., Lindner, J., Magnuson, M.A., Kong, Y.-Y, Serup, P., Ahnfelt-Rønne, J., Jensen, J.N. (2012) Mind bomb 1 is required for pancreatic b-cell formation. Proc. Natl. Acad. Sci. USA in press. (2) Imayoshi, I., Tabuchi, S., Hirano, K., Sakamoto, M., Kitano, S., Miyachi, H., Yamanaka, A., and Kageyama, R. (2012) Light-induced silencing of neural activity in Rosa26 knock-in mice conditionally expressing the microbial halorhodopsin enphr2.0. Neurosci. Res. in press. (3) Imayoshi, I., Hirano, K., Kitano, S., Mitachi, H., and Kageyama, R. (2012) In vivo evaluation of PhiC31 recombinase activity in transgenic mice. Neurosci. Res. in press.

4 (4) Imayoshi, I., Hirano, K., Sakamoto, M., Miyoshi, G., Imura, T., Kitano, S., Mitachi, H., and Kageyama, R. (2012) A multifunctional teal-fluorescent Rosa26 reporter mouse line for Cre- and Flp-mediated recombination. Neurosci. Res. 73, DOI: /j.neures (5) Sparrow, D.B., Chapman, G., Smith, A.J., Mattar, M.Z., Major, J.A., O Reilly, V.C., Saga, Y., Zackai, E.H., Dormans, J.P., Alman, B.A., McGregor, L., Kageyama, R., Kusumi, K., and Dunwoodie, S.L. (2012) A mechanism for gene-environment interaction in the etiology of congenital scoliosis. Cell 149, DOI: /j.cell (6) Ueo, T., Imayoshi, I., Kobayashi, T., Ohtsuka, T., Seno, H., Nakase, H., Chiba, T., and Kageyama, R. (2012) The role of Hes genes in intestinal development, homeostasis and tumor formation. Development 139, DOI: /dev (7) Bae, Y.-H., Park, H.-J., Kim, S.R., Kim, J.Y., Kang, Y. Kim, J.A., Wee, H.-J., Kageyama, R., Jung, J.S., Bae, M.-K., and Bae, S.-K. (2011) Notch1 mediates visfatin-induced FGF-2 upregulation and endothelial angiogenesis. Cardiovasc. Res. 89, DOI: /cvr/cvq276 (8) Matsumoto, A., Onoyama, I., Sunabori, T., Kageyama, R., Okano, H., and Nakayama, K.I. (2011) Fbxw7-dependent degradation of Notch is required for control of syemness and neuronal-glial differentiation in neural stem cells. J. Biol. Chem. 286, DOI: /jbc.M (9) Ohtsuka, T., Shimojo, H., Matsunaga, M., Watanabe, N., Kometani, K., Minato, N., and Kageyama, R. (2011) Gene expression profiling of neural stem cells and identification of regulators of neural differentiation during cortical development. Stem Cells 29, DOI: /stem.731 (10) Shibata, K., Yamada, H., Sato, T,, Dejima, S., Nakamura, M., Ikawa, T., Hara, H., Yamasaki, S., Kageyama, R., Iwakura, Y., Kawamoto, H., Toh, H., and Yoshikai, Y. (2011) Notch-Hes1 pathway induces IL-17-producing gd T cells. Blood 118, DOI: /blood (11) Niwa, Y., Shimojo, H., Isomura, A., González, A., Miyachi, H., and Kageyama, R. (2011) Different types of oscillations in Notch and Fgf signaling regulate the spatiotemporal periodicity of somitogenesis. Genes & Dev. 25, DOI: /gad (12) Sakamoto, M., Imayoshi, I., Ohtsuka, T., Yamaguchi, M., Mori, K., and Kageyama, R. (2011) Continuous neurogenesis in the adult forebrain is required for innate olfactory responses. Proc. Natl. Acad. Sci. USA 108, DOI: /pnas (13) Tateya, T., Imayoshi, I., Tateya, I., Ito, J., and Kageyama, R. (2011) Cooperative functions of Hes/Hey genes in auditory hair cell and supporting cell development. Dev. Biol. 352, DOI: /j.ydbio (14) Takashima, Y., Ohtsuka, T., González, A., Miyachi, H., and Kageyama, R. (2011) Intronic delay is essential for oscillatory expression in the segmentation clock. Proc. Natl. Acad. Sci. USA 108, DOI: /pnas (15) Ikeda, K., Kageyama, R., Suzuki, Y., and Kawakami, K. (2010) Six1 is indispensable for production of functional apical and basal progenitors during olfactory epithelial development. Int. J. Dev. Biol. 54, DOI: /ijdb ki (16) Kobayashi, T. and Kageyama, R. (2010) Hes1 regulates embryonic stem cell differentiation by suppressing Notch signaling. Genes to Cells 15, DOI: /j x (17) Karlsson, C., Brantsing, C., Kageyama, R., and Lindahl, A. (2010) HES1 and HES5 are dispensable for cartilage and endochondral bone formation. Cells Tissue Organs 192, DOI: / (18) Inoue, T., Coles, B., Dorval, K., Bremner, R., Bessho, Y., Kageyama, R., Hino, S., Matsuoka, M., Craft, C., McInnes, R., Temblay, F., Prusky, G., Tano, Y., and van der Kooy, D. (2010) Maximizing functional photoreceptor differentiation from adult human retinal stem cells. Stem Cells 28, DOI: /stem.27 (19) Shimizu, T., Nakazawa, M., Kani, S., Bae, Y.-K., Shimizu, T., Kageyama, R., and Hibi, M. (2010) Zinc-finger genes Fezf1 and Fezf2 control neuronal differentiation by repressing Hes5 expression in forebrain. Development 137, DOI: /dev (20) Imayoshi, I., Sakamoto, M., Yamaguchi, M., Mori, K., and Kageyama, R. (2010) Essential roles of Notch signaling in maintenance of neural stem cells in the developing and adult brains. J. Neurosci. 30, DOI: / JNEUROSCI (21) Nagahara, H., Ma, Y., Takenaka, Y., Kageyama, R., and Yoshikawa, K. (2009) Spatio-temporal pattern in somitogenesis: a non-turing scenario with wave propagation.

5 Physical Rev. E. 80, (1-7). DOI: /PhysRevE (22) Arai, M., Masada, A., Ohtsuka, T., Kageyama, R., and Ishibashi, M. (2009) The first Hes1 dimer inhibitors from natural products. Bioorganic & Medicinal Chemistry Letters 19, DOI: /j.bmcl (23) Murata, J., Ohtsuka, T., Tokunaga, A., Nishiike, S., Inohara, H., Okano, H., and Kageyama, R. (2009) Notch-Hes1 pathway contributes to the cochlear prosensory formation potentially through the transcriptional down-regulation of p27(kip1). J. Neurosci. Res. 87, DOI: /jnr (24) Kobayashi, T., Mizuno, H., Imayoshi, I., Furusawa, C., Shirahige, K., and Kageyama, R. (2009) The cyclic gene Hes1 contributes to diverse differentiation responses of embryonic stem cells. Genes & Dev. 23, DOI: /gad (25) González, A., and Kageyama, R. (2009) Hopf Bifurcation in the Presomitic Mesoderm during the Mouse Segmentation. J. Theor. Biol. 259, DOI: /j.jtbi 'µ, ˇ*1 $+4#ˇåî.. Kageyama, R.: Spatiotemporal regulation of somitogenesis by the oscillator networks of the segmentation clock. Annual Meeting of American Society for Cell Biology, Denver, USA, 12 & 3 (-12 & 7 (, Kageyama, R.: The role of Notch signaling in proliferation and differentiation of neural stem cells. Fondation Des Treilles, France, 10 & 24 (-10 & 28 (, Kageyama, R.: T The oscillator networks in the somite segmentation clock. The Notch Meeting V, Athens, Greece, 10 & 2 (-10 & 6 (, Kageyama, R.: The role of Notch signaling in embryonic and adult neural stem cells. The Company of Biologists Workshops, West Sussex, UK, 9 & 18 (-9 & 21 (, Kageyama, R.: Essential roles of Notch signaling in embryonic and adult neural stem cells. 23 rd Biennial Meeting of the International Society for Neurochemistry, Athens, Greece, 8 & 28 (-9 & 1 (, Kageyama, R.: Ultradian oscillations in somite segmentation and other biological events. The 6 th bhlh Symposium. Shanghai, ChinaJ5 & 16 (-5 & 17 (, Kageyama, R.: U The role of Notch signling in proliferation and differentiation of adult neural stem cellsjjoint Japan-Australia-New Zealand Symposium --- Building a Functional BrainJAuckland, New ZealandJÆ&# (, Kageyama R.: Functional significance of neurogenesis in the olfactory bulb. Keystone Symposium --- Adult Neurogenesis, Taos, USA, Æ& (-Æ&Æ$(, Kageyama, R.: Essential roles of Notch signaling in embryonic and adult neural stem cellsj Notch and Stem CellsJAthens, GreeceJ10 & 3 (-10 & 6 ( Kageyama, R.: The significance and mechanism of ultradian oscillations in somite segmentation and other biological eventsj International Workshop on Timing and Dynamics in Biological SystemsJDresden, GermanyJ9 & 26 (-9 & 30 ( Kageyama, R.: The role of Notch signalingin embryonic and adult neural stem cells J Perspectives of Stem CellsJSao Paulo, BrazilJ 9 & 20 (-9 & 24 ( Kageyama, R.: The role of Notch signaling in embryonic and adult neural stem cellsjenp Neural Stem Cell MeetingJAbbaye des Vaux de Cernay, FranceJ6 & 17 (-6 & 19 ( Kageyama R.: The role of Notch signaling in embryonic and adult neurogenesis J 18 th Biennial Meeting of the International Society for Developmental Neuroscience J Lisbon, PortugalJ6 & 6 (-6 & 9 ( Kageyama, R.: The role of Hes1 oscillations in regulation of stem/progenitor cells. The Notch Meeting. Athens, Greece, Sept 27-Oct 1, Kageyama, R.: Ultradian oscillators in somite segmentation and other biological events. Symposium on Developmental Biology, London, UK, June 17-19, Kageyama, R.: The role of Hes1 in proliferation and differentiation of neural stem cells. EMBO Workshop/ 5 th International Symposium on bhlh transcription factors. London, UK, May 7-8, Kageyama, R.: Ultradian oscillators in somite segmentation and other biological events. 8 th International Conference on Information Processing in Cells and Tissues, Ascona, Switzerland, April 5-9, '.*1 x+4 (1) Kageyama, R., Niwa, Y., Shimojo, H., Kobayashi, T., and Ohtsuka, T. (2010) Ultradian oscillations in Notch signaling regulate dynamic biological events. Curr. Top. Dev. Biol. 92C, DOI:

6 /S (10) (2) Kageyama, R., Niwa, Y., and Shimojo, H. (2010) Developmental timing and oscillating gene expression. McGraw-Hill 2010 YearBook of Science & Technology, pp (3) Niwa, Y., Shimojo, H., and Kageyama, R. (2009) Ultradian oscillation networks in somite segmentation and other biological events. In Systems Biology (Eds, S. Nakanishi, R. Kageyama, and D. Watanabe) Springer, pp 'Ç/0Ç1* 2Å3 41 # v^æ ødc. ø. È 8Íy BÆ59:; <J=>?M µybcd µ ÉE5EF GH5E Å3%&(5!"#Æ%I&ÆJ( Akœ.Ô5Ak Z!"67EopG89:;<=>} ãf åî TløEµ0 ÊGY5CD=X 1!" î % Z & (!îm ]4 J +,}~ (1)+,#ˇÆ ü9:ü; <(KAGEYAMA RYOICHIRO) CD µäqiår+,ÿägq ü+,ægh5p ##$xj (2)+, óæ üîx ü (3)%&+,Æ üüîx 5657v^æ ødc. ø. È 8Íy BÆ59:; <J=>?M 1@Æ5AÍ µybcd µ ÉE5EF GH5öèìKLöî M K ñî M Å3%&(5!"##%I&Æ'( Akœ.Ô5Aœ 2NQ 'ˆ.O* P:êQ:G" PRÄRnS M!T`KLM UâäM xv^æ ø.7 î ÈløEÿ,5W(=X1!" îm % Y & MZ ([\!Y ]4JCD=X1Y & MZ ([\!Y ]4J(^ _=X1Y & Mñ (! ]4J`(=X1Y & MZ ([\!a ]4o bc=x1y & MZ ([\!î ]4 î!v^æ øeopg UâäM ntd:te <.?@5àUf g Idhü i»<r jëíkü!" îî %$&x(!" : ; < = > c T m n o p5àuf g Idhü i»<r jëíkü! " îî %J&#J(! lw KLMxJmêAnoE}i <C;<E G ). {xµ 5W( =X1!" î %#&p(4jcd=x1# &p(w\4