HOME > Members > GCOE Organizing Members > Kozo Kaibuchi MD, PhD


Kozo Kaibuchi MD, PhDProfessor, Department of Cell Pharmacology, Nagoya University Graduate School of Medicine


Specialized field

Cell biology

Career Summary

1980
Graduated from Kobe University School of Medicine
1984
Completed Graduate School of Kobe University School of Medicine
(Supervised by Prof. Y. Nishizuka)
1985
DNAX Research Institute of Molecular and Cellular Biology
1989
Department of Biochemistry, Kobe University School of Medicine, Assistant Professor
1990
Department of Biochemistry, Kobe University School of Medicine, Associate Professor
1994
Division of Signal Transduction, Nara Institute of Science and Technology, Professor
2000
Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Professor

Research Theme

Elucidation of mental and neurological disorders via investigation of neuronal polarity

Research Summary

Specific Aims

The schizophrenias have a lifetime prevalence of approximately 1% in the general population and give a serious and intractable mental disorder. It has been still uncleared the molecular mechanism of the schizophrenia onset to date. Recently, the assumption of the onset has been potentially confident of the developmental disability on central nervous system. Furthermore, schizophrenia is known to be multifactorial disease participitating in not only a genetic factor but also an environmental factor during embryonic stage, perinatal stage, or adolescence. Many genomic analyses of schizophrenia patients have reported the candidate genes for onset risk of the symptom, resulting DISC1 is the most possible factor by the evidence of Scottish-descent analysis. In spite of many studies of DISC1, the exact roles of DISC1 in vivo remain largely unknown because DISC1 knockout mice and the well-characterized antibody to DISC1 are not available to date. We have focused on the signal network among the onset risk genes of DISC1 and DISC1 interacting proteins and analysed globally the molecular interaction of signal transduction proteins to be constituted with the network in various types of neurons, in purpose of the clarification of the pathogenic mechanism of schizophrenia.

Achievement

1. DISC1 regulates the transport of specific neuronal messenger RNA

DISC1 is a susceptibility gene for major psychiatric disorders. DISC1 is implicated in neuronal development like neurogenesis, neuronal migration, axon formation, dendritic arborization and synapse formation. We have identified the DISC1-interacting proteins by proteome analysis and found a trimeric complex composed of DISC1, Hzf and IP3 receptor 1 (IP3R1) mRNA. DISC1 directly associated with IP3R1 mRNA and was co-transported into dendrites. The impairments of DISC1 functions prohibited dendritic transport and BDNF-induced translation of IP3R1 mRNA. DISC1 together with Hzf interact with a specific mRNAs such as IP3R1 mRNA and regulates their dendritic transport and translation as a component of RNA granules. Furthermore, we have identified KALRN mRNA, which belongs to RhoGEF family and is an important molecule for synapse formation, as a DISC1 binding mRNA.

2. Generation and analysis of DISC1 knockout mouse as model mice for schizophrenia

To validate the pathogenic mechanisms of mental retardation such as schizophrenia, many model mice have been generated in the world. So we also produced the DISC1-deficient mice to elucidate the molecular nature of the psychiatric disorders. Concretely, we had deleted the DISC1 gene by skipping the exon 2 and 3 and made the DISC1 specific antibodies in plural lines for inspection of the validity of the DISC1 mutant mice. As a result of that, we succeeded the DISC1 antibodies better than ones in the past both in the specificity and sensitivity. We confirmed the DISC1 knockout in the brain tissue or hippocampal culture cell lines by immunoblot analysis. Moreover, by our immunohistochemical analyses, we found DISC1 distributed in developing brain containing hippocampus and cerebral cortex. Although there were not any remarkable defects on pathological finding of the DISC1 mutant brain, some significant differences were noticed in the behavioral and electrophysiological analyses. The DISC1-deficient mice manifested abnormality of emotional behavior in the elevated-plus maze test and cliff avoidance test, suggesting that deficiency of DISC1 may result in lower anxiety and/or higher impulsivity. Both DISC1-deficient mice and DISC1 specific antibodies serve as powerful tool to dissect the pathophysiological functions of DISC1. We have been elucidating the biological function of DISC1 by crossbreeding with other mutant mice, and by cellular biological analyses described below.

3. DISC1 intracellular localization and molecular function analysis

To elucidate the pathogenic mechanism of schizophrenia, we have analyzed DISC1 localization and function in neuronal cells. Our anti-DISC1 antibody enabled us to observe clear localization to Golgi apparatus in cultured neuron prepared from developing hippocampus. We hypothesized that DISC1 would be involved in vesicular transport of various proteins and mRNAs which maintain neuronal function. Previously, we have identified direct interaction of DISC1 and Neuregulin-1, which is a ligand of ErbB3 and ErbB4. To understand the sense of their association, we have attempted to analyze their common interacting proteins. As a result of the comprehensive screenings, we have identified ARF and AP family proteins, which have essential roles for intracellular vesicle trafficking. Moreover, we have revealed direct binding of DISC1 and ARFs to pro-Neuregulin-1 intracellular domain, resulting in the molecular mechanism of its budding and transport.

Principal Research Achievement

  1. Watanabe K, Akimoto Y, Yugi K, Uda S, Chung J, Nakamuta S, Kaibuchi K, Kuroda S: Latent process genes for cell differentiation are common decoders of neurite extension length. J Cell Sci, in press (2012)
  2. Nishioka T, Nakayama M, Amano M, Kaibuchi K: Proteomic Screening for Rho-kinase Substrates by Combining Kinase and Phosphatase Inhibitors with 14-3-3zeta Affinity Chromatography. Cell Struct Funct, 37, 39-48 (2012)
  3. Kuroda K, Yamada S, Tanaka M, Iizuka M, Yano H, Mori D, Tsuboi D, Nishioka T, Namba T, Iizuka Y, Kubota S, Nagai T, Ibi D, Wang R, Enomoto A, Isotani-Sakakibara M, Asai N, Kimura K, Kiyonari H, Abe T, Mizoguchi A, Sokabe M, Takahashi M, Yamada K, Kaibuchi K: Behavioral alterations associated with targeted disruption of exons 2 and 3 of the Disc1 gene in the mouse. Hum Mol Genet, 20, 4666-4683 (2011)
  4. Nakamuta S, Funahashi Y, Namba T, Arimura N, Picciotto MR, Tokumitsu H, Soderling TR, Sakakibara A, Miyata T, Kamiguchi H, Kaibuchi K: Local application of neurotrophins specifies axons through inositol 1,4,5-trisphosphate, calcium, and Ca2+/calmodulin-dependent protein kinases. Sci Signal, 4, ra76 (2011)
  5. Namba T, Ming GL, Song H, Waga C, Enomoto A, Kaibuchi K, Kohsaka S, Uchino S: NMDA receptor regulates migration of newly generated neurons in the adult hippocampus via Disrupted-In-Schizophrenia 1 (DISC1). J Neurochem, 118, 34-44 (2011)
  6. Sato K, Watanabe T, Wang S, Kakeno M, Matsuzawa K, Matsui T, Yokoi K, Murase K, Sugiyama I, Ozawa M, Kaibuchi K: Numb controls E-cadherin endocytosis through p120 catenin with aPKC. Mol Biol Cell, 22, 3103-3119 (2011)
  7. Li W, Miki T, Watanabe T, Kakeno M, Sugiyama I, Kaibuchi K, Goshima G: EB1 promotes microtubule dynamics by recruiting Sentin in Drosophila cells. J Cell Biol, 193, 973-983 (2011)
  8. Wang Y, Kaneko N, Asai N, Enomoto A, Isotani-Sakakibara M, Kato T, Asai M, Murakumo Y, Ota H, Hikita T, Namba T, Kuroda K, Kaibuchi K, Ming GL, Song H, Sawamoto K, Takahashi M: Girdin is an intrinsic regulator of neuroblast chain migration in the rostral migratory stream of the postnatal brain. J Neurosci, 31, 8109-8122 (2011)
  9. Naoki H, Nakamuta S, Kaibuchi K, Ishii S: Flexible search for single-axon morphology during neuronal spontaneous polarization. PLoS One, 6, e19034 (2011)
  10. Doe CQ, Kaibuchi K: Neuronal polarity in 2011. Dev Neurobiol, 71, 401-402 (2011)
  11. Morinaka A, Yamada M, Itofusa R, Funato Y, Yoshimura Y, Nakamura F, Yoshimura T, Kaibuchi K, Goshima Y, Hoshino M, Kamiguchi H, Miki H: Thioredoxin mediates oxidation-dependent phosphorylation of CRMP2 and growth cone collapse. Sci Signal, 4, ra26 (2011)
  12. Routray, C., Liu, C., Yaqoob, U., Billadeau, D. D., Bloch, K. D., Kaibuchi, K., Shah, V. H., and Kang, N. Protein kinase G signaling disrupts Rac1 dependent focal adhesion assembly in liver specific pericytes, Am J Physiol Cell Physiol, 301, C66-74 (2011)
  13. Qadota, H., Miyauchi, T., Nahabedian, J. F., Stirman, J. N., Lu, H., Amano, M., Benian, G. M., and Kaibuchi, K. PKN-1, a Homologue of Mammalian PKN, Is Involved in the Regulation of Muscle Contraction and Force Transmission in C. elegans, J Mol Biol, 407, 222-231. (2011)
  14. Namba, T., Nakamuta, S., Funahashi, Y., and Kaibuchi, K. The role of selective transport in neuronal polarization, Dev Neurobiol, 71, 445-457 (2011)
  15. Kobayashi, K., Masuda, T., Takahashi, M., Miyazaki, J., Nakagawa, M., Uchigashima, M., Watanabe, M., Yaginuma, H., Osumi, N., and Kaibuchi, K. Rho/Rho-kinase signaling pathway controls axon patterning of a specified subset of cranial motor neurons, Eur J Neurosci, 33, 612-621. (2011)
  16. Katsumi, A., Kiyoi, H., Abe, A., Tanizaki, R., Iwasaki, T., Kobayashi, M., Matsushita, T., Kaibuchi, K., Senga, T., Kojima, T., Kohno, T., Hamaguchi, M., and Naoe, T. FLT3/ ITD regulates leukaemia cell adhesion through alpha4beta1 integrin and Pyk2 signalling, Eur J Haematol, 86, 191-198. (2011)
  17. Ikeda, M., Aleksic, B., Kinoshita, Y., Okochi, T., Kawashima, K., Kushima, I., Ito, Y., Nakamura, Y., Kishi, T., Okumura, T., Fukuo, Y., Williams, H. J., Hamshere, M. L., Ivanov, D., Inada, T., Suzuki, M., Hashimoto, R., Ujike, H., Takeda, M., Craddock, N., Kaibuchi, K., Owen, M. J., Ozaki, N., O'Donovan, M. C., and Iwata, N. Genome-wide association study of schizophrenia in a Japanese population, Biol Psychiatry, 69, 472-478. (2011)
  18. Heil, A., Nazmi, A. R., Koltzscher, M., Poeter, M., Austermann, J., Assard, N., Baudier, J., Kaibuchi, K., and Gerke, V. S100P Is a Novel Interaction Partner and Regulator of IQGAP1, J Biol Chem, 286, 7227-7238. (2011)
  19. Takefuji, M., Asano, H., Mori, K., Amano, M., Kato, K., Watanabe, T., Morita, Y., Katsumi, A., Itoh, T., Takenawa, T., Hirashiki, A., Izawa, H., Nagata, K., Hirayama, H., Takatsu, F., Naoe, T., Yokota, M., and Kaibuchi, K. Mutation of ARHGAP9 in patients with coronary spastic angina, J Hum Genet, 55, 42-49. (2010)
  20. Namba, T., and Kaibuchi, K. Switching DISC1 function in neurogenesis: Dixdc1 selects DISC1 binding partners, Dev Cell, 19, 7-8. (2010)
  21. Nakano, A., Kato, H., Watanabe, T., Min, K. D., Yamazaki, S., Asano, Y., Seguchi, O., Higo, S., Shintani, Y., Asanuma, H., Asakura, M., Minamino, T., Kaibuchi, K., Mochizuki, N., Kitakaze, M., and Takashima, S. AMPK controls the speed of microtubule polymerization and directional cell migration through CLIP-170 phosphorylation, Nat Cell Biol, 12, 583-590. (2010)
  22. Nagai, T., Kitahara, Y., Shiraki, A., Hikita, T., Taya, S., Kaibuchi, K., and Yamada, K. Dysfunction of dopamine release in the prefrontal cortex of dysbindin deficient sandy mice: an in vivo microdialysis study, Neurosci Lett, 470, 134-138. (2010)
  23. Kushima, I., Nakamura, Y., Aleksic, B., Ikeda, M., Ito, Y., Shiino, T., Okochi, T., Fukuo, Y., Ujike, H., Suzuki, M., Inada, T., Hashimoto, R., Takeda, M., Kaibuchi, K., Iwata, N., and Ozaki, N. Resequencing and Association Analysis of the KALRN and EPHB1 Genes And Their Contribution to Schizophrenia Susceptibility, Schizophr Bull, (2010)
  24. Kubo, K., Tomita, K., Uto, A., Kuroda, K., Seshadri, S., Cohen, J., Kaibuchi, K., Kamiya, A., and Nakajima, K. Migration defects by DISC1 knockdown in C57BL/6, 129X1/SvJ, and ICR strains via in utero gene transfer and virus-mediated RNAi, Biochem Biophys Res Commun, 400, 631-637. (2010)
  25. Itoh, N., Nakayama, M., Nishimura, T., Fujisue, S., Nishioka, T., Watanabe, T., and Kaibuchi, K. Identification of focal adhesion kinase (FAK) and phosphatidylinositol 3-kinase (PI3-kinase) as Par3 partners by proteomic analysis, Cytoskeleton (Hoboken) , 67, 297-308. (2010)
  26. Iritani, S., Sekiguchi, H., Habuchi, C., Hikita, T., Taya, S., Kaibuchi, K., and Ozaki, N. Immunohistochemical study of vesicle monoamine transporter 2 in the hippocampal region of genetic animal model of schizophrenia, Synapse, 64, 948-953. (2010)
  27. Ikeda, M., Aleksic, B., Kinoshita, Y., Okochi, T., Kawashima, K., Kushima, I., Ito, Y., Nakamura, Y., Kishi, T., Okumura, T., Fukuo, Y., Williams, H. J., Hamshere, M. L., Ivanov, D., Inada, T., Suzuki, M., Hashimoto, R., Ujike, H., Takeda, M., Craddock, N., Kaibuchi, K., Owen, M. J., Ozaki, N., O'Donovan, M. C., and Iwata, N. Genome-wide association study of schizophrenia in a Japanese population, Biol Psychiatry, 69, 472-478. (2010)
  28. Amano, M., Nakayama, M., and Kaibuchi, K. Rho-kinase/ROCK: A key regulator of the cytoskeleton and cell polarity, Cytoskeleton (Hoboken) , 67, 545-554. (2010)
  29. Matsumoto S, Fumoto K, Okamoto T, Kaibuchi K, and Kikuchi A. Binding of APC and dishevelled mediates Wnt5a-regulated focal adhesion dynamics in migrating cells. EMBO J, 29, 1192-1204 (2010)
  30. Terawaki S, Kitano K, Mori T, Zhai Y, Higuchi Y, Itoh N, Watanabe T, Kaibuchi K, Hakoshima T. The PHCCEx domain of Tiam1/2 is a novel protein- and membrane-binding module. EMBO J, 29, 236-250 (2010)
  31. Amano M, Tsumura Y, Taki K, Harada H, Mori K, Nishioka T, Kato K, Suzuki T, Nishioka Y, Iwamatsu A, Kaibuchi K. A proteomic approach for comprehensively screening substrates of protein kinases such as Rho-kinase. PLoS One, 14, 5, e8704 (2010)
  32. Watanabe T, Noritake J, Kakeno M, Matsui T, Harada T, Wang S, Itoh N, Sato K, Matsuzawa K, Iwamatsu A, Galjart N, Kaibuchi K. Phosphorylation of CLASP2 by GSK-3beta regulates its interaction with IQGAP1, EB1 and microtubules. J Cell Sci, 122, 2969-2979 (2009)
  33. Mori K, Amano M, Takefuji M, Kato K, Morita Y, Nishioka T, Matsuura Y, Murohara T,  Kaibuchi K. Rho-kinase contributes to sustained RhoA activation through phosphorylation of p190A RhoGAP. J Biol Chem, 284, 5067-5076 (2009)
  34. Hikita T, Taya S, Fujino Y, Taneichi-Kuroda S, Ohta K, Tsuboi D, Shinoda T, Kuroda K, Funahashi Y, Uraguchi-Asaki J, Hashimoto R, Kaibuchi K. Proteomic analysis reveals novel binding partners of dysbindin, a schizophrenia-related protein. J Neurochem, 110, 1567-1574, (2009)
  35. Hata K, Kaibuchi K, Inagaki S, Yamashita T. Unc5B associates with LARG to mediate the action of repulsive guidance molecule. J Cell Biol, 184, 737-750 (2009)
  36. Enomoto A, Asai N, Namba T, Wang Y, Kato T, Tanaka M, Tatsumi H, Taya S, Tsuboi D, Kuroda K, Kaneko N, Sawamoto K, Miyamoto R, Jijiwa M, Murakumo Y, Sokabe M, Seki T, Kaibuchi K, Takahashi M. Roles of disrupted-in-schizophrenia 1-interacting protein girdin in postnatal development of the dentate gyrus. Neuron, 63, 774-787 (2009)
  37. Arimura N, Kimura T, Nakamuta S, Taya S, Funahashi Y, Hattori A, Shimada A, Menager C, Kawabata S, Fujii K, Iwamatsu A, Segal R A, Fukuda M, Kaibuchi K. Anterograde transport of TrkB in axons is mediated by direct interaction with Slp1 and Rab27. Dev Cell, 16, 675-686 (2009)
  38. Arimura N, Hattori A, Kimura T, Nakamuta S, Funahashi Y, Hirotsune S, Furuta K, Urano T, Toyoshima YY, Kaibuchi K. CRMP-2 directly binds to cytoplasmic dynein and interferes with its activity. J Neurochem, 111, 380-390 (2009)
  39. Yamashiro S, Yamakita Y, Totsukawa G, Goto H, Kaibuchi K, Ito M, Hartshorne D J, Matsumura F. Myosin phosphatase-targeting subunit 1 regulates mitosis by antagonizing polo-like kinase 1. Dev Cell, 14, 787-797 (2008)
  40. Sugimoto M, Inoko A, Shiromizu T, Nakayama M, Zou P, Yonemura S, Hayashi Y, Izawa I, Sasoh M, Uji Y, Kaibuchi K, Kiyono T, Inagaki M. The keratin-binding protein Albatross regulates polarization of epithelial cells. J Cell Biol, 183, 19-28 (2008)
  41. Ikeda M et al. Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia. Hum. Mol. Genet. in press (2008)
  42. Nakayama M et al. Rho-kinase phosphorylates PAR-3 and disrupts PAR complex formation. Dev Cell 13: 205-215 (2008)
  43. Nishimura T et al. Numb controls integrin endocytosis for directional cell migration with aPKC and PAR-3. Dev. Cell 13: 15-28 (2007)
  44. Arimura N et al. Neuronal polarity: from extracellular signals to intaracellular mechanism. Nature Rev. Neurosci. 8: 194-205 (2007)
  45. Taya S et al. DISC1 regulates the transport of the NUDEL/LIS1/14-3-3epsilon complex through kinesin-1. J Neurosci. 27: 15-26 (2007)
  46. Kim WY et al. Essential roles of GSK-3s and GSK-3-primed substrates in neurotrophin-induced and hippocampal axon growth Neuron 52: 981-996 (2006)
  47. Yoshimura T et al. GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity. Cell 120: 137-149 (2005)
  48. Nishimura T et al. PAR-6-PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1. Nature Cell Biol. 7: 270-277 (2005)
  49. Watanabe T et al. Interaction with IQGAP1 Links APC to Rac1, Cdc42, and Actin Filaments during Cell Polarization and Migration. Dev. Cell 7: 871-883 (2004)
  50. Nishimura T et al. Role of the PAR-3-KIF3 complex in the establishment of neuronal polarity. Nature Cell Biol. 6: 328-334 (2004)
  51. Nishimura T et al. CRMP-2 regulates polarized Numb-mediated endocytosis for axon growth. Nature Cell Biol. 5: 819-826 (2003)
  52. Fukata M et al. Rac1 and Cdc42 capture microtub ules through IQGAP1 and CLIP-170. Cell 109: 873-885 (2002)
  53. Fukata Y et al. CRMP-2 binds to tubulin heterodimers to promote microtubule assembly. Nature Cell Biol. 4: 583-591 (2002)
  54. Inagaki N et al. CRMP-2 induces axons in cultured hippocampal neurons. Nature Neurosci. 4: 781-782 (2001)
  55. Kaibuchi K et al. Regulation of the cytoskeleton and cell adhesion by the Rho family GTPases in mammalian cells. Annual Rev. Biochem. 68: 459-486 (1999)
  56. Kuroda S et al. Role of IQGAP1, a target of the small GTPases Cdc42 and Rac1, in regulation of E-cadherin-mediated cell-cell adhesion. Science 281: 832-835 (1998)
  57. Amano M et al. Formation of actin stress fibers and focal adhesions enhanced by Rho-kinase. Science 275: 1308-1311 (1997)
  58. Kimura K et al. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science 273: 245-258 (1996)
  59. Amano M et al. Identification of a putative target for Rho as the serine-threonine kinase protein kinase N. Science 271: 648-650 (1996)

Award

Scientific Resarch Award of the Japanese Cancer Association (1992)
NAIST Scientific Research Award (1998)
ISI highly cited researchers (2000)
Yomiuri-Tokai Medical Award (2008, The Yomiuri Shimbun)

PAGE TOP