Cell biology

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

Elucidation of mental and neurological disorders via investigation of neuronal polarity

We have investigated functions and regulatory mechanisms of Rho family GTPases, and revealed their roles in organization of cytoskeleton, migration, adhesion and polarization. （Science 1996,1997,1998; Annu. Rev. Biochem. 1999; Nat. Rev., Mol. Cell. Biol. 2001）

We are currently interested in mechanisms that control the establishment of neuronal polarity, and roles of polarity-regulating molecules in pathogenesis of neuronal and psychiatric disorders. A cardinal feature of neurons is the morphological polarity of neurons with serious functional implications. Typically, a neuron has a single axon and several dendrites. Neuronal polarity is essential for the unidirectional signal flow from dendrites to axons in neurons. These two distinct cellular structures are fundamental for neuronal function, as they enable neurons to receive and transmit electrical signals. However, the molecular mechanisms that underlie the neuronal polarization were unclear until a decade ago. We previously found that collapsin response mediator protein-2 (CRMP-2) plays a critical role in the axon specification and elongation (Nat. Neurosci. 2001). CRMP-2-activity is regulated by PI3K/Akt/GSK-3b pathway （Cell 2005）. CRMP-2 functions as “cargo receptors” to link cargo molecules, including tubulin, Numb and Sra-1, with Kinesin-1, a microtubules-dependent motor protein. CRMP-2 is required to transport these cargo molecules to distal part of axon (Nat. Cell Biol. 2002, 2003, 2004, 2005; Neuron 2006; Nat. Rev. Neurosci. 2007). CRMP-2 is also introduced as a new target for the treatment of Alzheimer’s disease, schizophrenia and nerve injury.

Schizophrenia is a complex mental disorder with a fairly high degree of heritability. Although the causes of schizophrenia remain largely unknown, it is now widely accepted that the disease is a neurodevelopmental and neurodegenerative disorder involving disconnectivity and disorder of the synapses. We are trying to clarify the pathology of schizophrenia via investigation of molecular functions of susceptibility genes for schizophrenia, including CRMP-2 and disrupted-in schizophrenia 1 (DISC1) in the neuronal polarization and development.

We searched for CRMP-2-interacting molecules from rat brain lysate by affinity-column chromatography followed with LC/MS/MS and immunoblotting, and identified synaptotagmin-like protein 1 (Slp1). Slp1 formed a complex with CRMP-2 and TrkB, a receptor of BDNF, in vivo. Because TrkB plays critical roles in the establishment of neuronal polarities, we speculate that CRMP-2 functions as polarity-regulating molecule via transport of TrkB to future axon. We are going to clarify the machinery underlying CRMP-2-mediated, axon specific transport of TrkB.

DISC1 is the most probable candidate genes for susceptibility to schizophrenia. We reported that DISC1 interacts with Kinesin-1, and functions as “cargo receptor” to transport DISC1-interacting molecules, the NUDEL/Lis1/14-3-3epsilon complex and Grb2, to distal part of axon and regulates axon elongation（J. Neurosci. 2007）. Recently, we identified several messenger ribonucleoproteins (mRNPs) as DISC1-interacting molecules. mRNP regulates localization and local translation of mRNA in neuronal cells. Identification of these mRNPs as DISC1-interacting molecules raised a possibility that DISC1 is involved in mRNA localization and local protein synthesis. We are going to investigate a role of DISC1 in the mRNA transport and local protein synthesis, especially in synapse.

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1. 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)
2. Nakayama M et al. Rho-kinase phosphorylates PAR-3 and disrupts PAR complex formation. Dev Cell 13: 205-215 (2008)
3. Nishimura T et al. Numb controls integrin endocytosis for directional cell migration with aPKC and PAR-3. Dev. Cell 13: 15-28 (2007)
4. Arimura N et al. Neuronal polarity: from extracellular signals to intaracellular mechanism. Nature Rev. Neurosci. 8: 194-205 (2007)
5. 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)
6. 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)
7. Yoshimura T et al. GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity. Cell 120: 137-149 (2005)
8. 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)
9. 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)
10. Nishimura T et al. Role of the PAR-3-KIF3 complex in the establishment of neuronal polarity. Nature Cell Biol. 6: 328-334 (2004)
11. Nishimura T et al. CRMP-2 regulates polarized Numb-mediated endocytosis for axon growth. Nature Cell Biol. 5: 819-826 (2003)
12. Fukata M et al. Rac1 and Cdc42 capture microtub ules through IQGAP1 and CLIP-170. Cell 109: 873-885 (2002)
13. Fukata Y et al. CRMP-2 binds to tubulin heterodimers to promote microtubule assembly. Nature Cell Biol. 4: 583-591 (2002)
14. Inagaki N et al. CRMP-2 induces axons in cultured hippocampal neurons. Nature Neurosci. 4: 781-782 (2001)
15. 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)
16. 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)
17. Amano M et al. Formation of actin stress fibers and focal adhesions enhanced by Rho-kinase. Science 275: 1308-1311 (1997)
18. Kimura K et al. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science 273: 245-258 (1996)
19. Amano M et al. Identification of a putative target for Rho as the serine-threonine kinase protein kinase N. Science 271: 648-650 (1996)

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)