Core Program members: Kazunobu Sawamoto
1992-1996: Department of Molecular Neurobiology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan. PhD (Doctor of Medical Science) awarded March 1996.
1990-1992: Department of Agricultural Chemistry, School of Agriculture, Meiji University, Kawasaki, Kanagawa, Japan. MA (Master of Agriculture) awarded March 1992.
1986-1990: Department of Agricultural Chemistry, School of Agriculture, Meiji University, Kawasaki, Kanagawa, Japan. BA (Bachelor of Agriculture) awarded March 1990.
2007-: Professor, Department of Developmental and Regenerative Biology, Nagoya City University Graduate School of Medical Sciences
2005-2007: Associate Professor, Bridgestone Laboratory of Developmental and Regenerative Neurobiology, Keio University School of Medicine
2003-2005: Assistant Professor, Department of Physiology, Keio University School of Medicine
2001-2003: Visiting Postdoc, Department of Neurological Surgery, University of California, San Francisco
1998-2003: Instructor, Division of Neuroanatomy, Department of Neuroscience, Biomedical Research Center, Osaka University Graduate School of Medicine
1997-1998: Instructor, Division of Neuroanatomy, Department of Neuroscience, Biomedical Research Center, Osaka University Medical School
1996-1997: Instructor, Department of Molecular Neurobiology, Institute of Basic Medical Sciences, University of Tsukuba
1995-1996: Research Fellow (Japan Society for the Promotion of Science), Department of Molecular Neurobiology, Institute of Medical Science, The University of Tokyo
Awards and Honors
2007: The Young Scientists' Prize, Ministry of Education, Culture, Sports, Science and Technology
2006: JSPS Prize, Japan Society for the Promotion of Science
2006: Medical Science Faculty and Alumni Grants, Keio University Medical Science Fund
2006: The Award for Young Investigator of Japanese Society for Neurochemistry
2004: Japan Neuroscience Society Young Investigator Award
2004: Sanshikai Award, Keio University School of Medicine
1999: Inoue Research Award for Young Scientists, Inoue Foundation of Science
1997: Young Investigator Award, University of Tsukuba
I have been studying various aspects of neural development since 1992 and am now focusing on neurogenesis and regeneration in the postnatal mammalian brain. While working as a G-COE member, I hope to focus mainly on the mechanisms of neuronal migration in the adult brain. In parallel, I will launch some new projects, including a genetic approach to identifying novel genes regulating adult neurogenesis and the development of novel methods for use in future projects. I hope to collaborate with other G-COE members, thereby enhancing each other's studies. I would also like to participate in the training of young scientists. Below, I have summarized my previous and ongoing research as well as my perspectives.
1) Adult neurogenesis and neuronal migration (since 2001)
There is increasing evidence that neural stem cells continuously produce new neurons in the adult mammalian brain. The subventricular zone (SVZ) of the lateral wall of the lateral ventricles is the largest germinal zone in the mature central nervous system. In the SVZ, there are at least four types of cells: neural stem cells, transit-amplifying cells, migrating neuroblasts and ciliated ependymal cells lining the ventricular wall. I have been studying the mechanisms regulating each of these cell types. Wnt/b-catenin signaling (Adachi et al., Stem Cells, 2007) has been implicated in the proliferation of stem cells and transit-amplifying cells. The neuroblasts generated by these progenitor cells migrate anteriorly into the olfactory bulbs. Recently, I contributed to a report describing how the migration of these neuroblasts parallels the flow of cerebrospinal fluid (CSF) (Sawamoto et al., Science, 2006). This study suggested that the beating of the cilia on the ependymal cells is required for directional CSF flow, the formation of chemorepulsive factors and the rostral migration of neuroblasts. We also found that the long-distance, directional migration of neuroblasts depends on the function of cdk5 (Hirota et al., J Neurosci, 2007). Many of the young neurons generated in the adult brain are known to die before their maturity. I contributed to a report demonstrating that the cholinergic system is involved in regulating the survival of young neurons (Kaneko et al., Genes Cells, 2006). To study whether these mechanisms are conserved between rodents and primates, we are studying neurogenesis and migration in the common marmoset (Callithrix jacchus) and Japanese monkey (Macaca fuscata).
2) Regeneration of the central nervous system (since 1999)
I have also been studying the regeneration potential of the central nervous system in adult mammalian brain using several models of diseases. Transplanted neural stem cells and/or mature neurons have been shown to cause functional recovery in rat models of Parkinson disease (Sawamoto et al., J Neurosci, 2001; Sawamoto et al., PNAS, 2001). More recently, I participated in a study examining the regeneration potential of subventricular zone cells after stroke. Using a mouse model of middle cerebral artery occlusion in combination with cre-loxP-based cell tracing methods, we found that subventricular-zone-derived neuroblasts migrate towards the damaged brain tissue along the blood vessels and regenerate mature striatal neurons in the ischemic striatum (Yamashita et al., J Neurosci, 2006; Ninomiya et al., Neurosci Lett., 2006). These results highlight the role of the SVZ in neuronal regeneration and its potential as an important therapeutic target for treating various neurological diseases.
3) Visualization, isolation, and transplantation of neural stem cells, neuronally committed progenitors, and dopaminergic neurons (since 1999)
Cell lineages in neurogenesis are poorly understood, partly because methodologies to identify and isolate cells based on the expression of cell surface markers have not been established. To solve this problem, I participated in the development of methods to identify and isolate specific neural cell types based on single or two-color fluorescent proteins expressed under the control of stage-specific neural promoter/enhancers.
The isolated cells were analyzed using an in vitro culture system and in vivo transplantation experiments. Using this strategy, we were able to visualize/isolate neural stem cells (Sawamoto et al., J. Neurosci., 2001), neuronally committed progenitors (Sawamoto et al., JNR, 2001), and midbrain dopaminergic neurons (Sawamoto et al., PNAS, 2001).
4) Mechanisms regulating cell proliferation, differentiation, survival and morphogenesis during Drosophila development (since 1992)
I participated in a study to identify and characterize Argos, a novel diffusible inhibitor of epidermal growth factor receptor (EGFR) (Sawamoto et al., Dev Biol., 1994; 1996; Taguchi et al., Genetics, 2000; Jin et al., MCB, 2000). Argos is required for the regulation of cellular differentiation in eye and wing vein development. We also found that the Argos-induced inhibition of Ras/MAPK signaling induces excessive cell death in the developing eye (Sawamoto et al., Cell Death Differ, 1998). Furthermore, we identified DRal, a possible downstream effector of Ras. Genetic studies indicate that DRal regulates developmental cell shape changes through the JNK pathway (Sawamoto et al., J Cell Biol, 1999; Sawamoto et al., Oncogene 1999). These results indicate that the EGFR signaling pathway plays various roles in animal development.
Okano, H. and Sawamoto, K. (2008)
Neural stem cells: Involvement in adult neurogenesis and CNS repair.
Philos. Trans. R. Soc. B. Biol. Sci. In Press.
Hirota, Y., Ohshima, T., Kaneko, N., Ikeda, M., Iwasato, T., Kulkarni, A., Mikoshiba, K., Okano, H., and Sawamoto, K. (2007)
Cyclin-dependent kinase 5 is required for control of neuroblast migration in the postnatal subventricular zone. J. Neurosci. 27, 12829-12838.
Adachi, K., Mirzadeh, Z., Sakaguchi, M., Yamashita, T., Nikolcheva, T., Gotoh, Y., Peltz, G., Gong, L., Kawase, T., Alvarez-Buylla, A., Okano, H., and Sawamoto, K. (2007)
b-catenin signaling promotes proliferation of progenitor cells in the adult mouse subventricular zone.
Stem Cells 25, 2827-2836.
Okano, H., Sakaguchi, M., Ohki, K., Suzuki, N. and Sawamoto, K. (2007)
Regeneration of the central nervous system using endogenous repair mechanisms.
J Neurochem. 102: 1459-1465.
Yamashita, T., Ninomiya, M., Hernandez Acosta, P., Garcia-Verdugo, J. M., Sunabori, T., Sakaguchi, M., Adachi, K., Kojima, T., Hirota, Y., Kawase, T., Araki, N., Abe, K., Okano, H., and Sawamoto, K. (2006).
Subventricular zone-derived neuroblasts migrate and differentiate into mature neurons in the post-stroke adult striatum.
J Neurosci 26, 6627-6636.
Kaneko, N., Okano, H., and Sawamoto, K. (2006).
Role of the cholinergic system in regulating survival of newborn neurons in the adult mouse dentate gyrus and olfactory bulb.
Genes Cells 11, 1145-1159.
Ninomiya, M., Yamashita, T., Araki, N., Okano, H., and Sawamoto, K. (2006).
Enhanced neurogenesis in the ischemic striatum following EGF-induced expansion of transit-amplifying cells in the subventricular zone.
Neurosci Lett 403, 63-67.
Sawamoto, K., Wichterle, H., Gonzalez-Perez, O., Cholfin, J. A., Yamada, M., Spassky, N., Murcia, N. S., Garcia-Verdugo, J. M., Marin, O., Rubenstein, J. L., Tessier-Lavigne, M., Okano, H., and Alvarez-Buylla, A. (2006).
New neurons follow the flow of cerebrospinal fluid in the adult brain.
Science 311, 629-632.
Sakaguchi, M., Shingo, T., Shimazaki, T., Okano, H. J., Shiwa, M., Ishibashi, S., Oguro, H., Ninomiya, M., Kadoya, T., Horie, H., Shibuya, A., Mizusawa, H., Poirier, F., Nakauchi, H., Sawamoto, K. and Okano, H. (2006).
A carbohydrate-binding protein, Galectin-1, promotes proliferation of adult neural stem cells.
Proc Natl Acad Sci U S A 103, 7112-7117.
Tonchev, A. B., Yamashima, T., Sawamoto, K., and Okano, H. (2006).
Transcription factor protein expression patterns by neural or neuronal progenitor cells of adult monkey subventricular zone.
Neuroscience 139, 1355-1367.
Tonchev, A. B., Yamashima, T., Sawamoto, K., and Okano, H. (2005).
Enhanced proliferation of progenitor cells in the subventricular zone and limited neuronal production in the striatum and neocortex of adult macaque monkeys after global cerebral ischemia.
J Neurosci Res 81, 776-788.
Yamashita, T., Sawamoto, K., Suzuki, S., Suzuki, N., Adachi, K., Kawase, T., Mihara, M., Ohsugi, Y., Abe, K., and Okano, H. (2005).
Blockade of interleukin-6 signaling aggravates ischemic cerebral damage in mice: possible involvement of Stat3 activation in the protection of neurons.
J Neurochem 94, 459-468.
Okano, H., Yoshizaki, T., Shimazaki, T., and Sawamoto, K. (2002)
Isolation and transplantation of dopaminergic neurons and neural stem cells.
Parkinsonism Relat Disord 9:23-28.
Sawamoto, K., Yamamoto, A., Kawaguchi, A., Yamaguchi, M., Mori, K., Goldman, S. A., and Okano, H. (2001).
Direct isolation of committed neuronal progenitor cells from transgenic mice coexpressing spectrally distinct fluorescent proteins regulated by stage-specific neural promoters.
J Neurosci Res 65, 220-227.
Sawamoto, K., Nakao, N., Kakishita, K., Ogawa, Y., Toyama, Y., Yamamoto, A., Yamaguchi, M., Mori, K., Goldman, S. A., Itakura, T., and Okano, H. (2001).
Generation of dopaminergic neurons in the adult brain from mesencephalic precursor cells labeled with a nestin-GFP transgene.
J Neurosci 21, 3895-3903.
Sawamoto, K., Nakao, N., Kobayashi, K., Matsushita, N., Takahashi, H., Kakishita, K., Yamamoto, A., Yoshizaki, T., Terashima, T., Murakami, F., Itakura, T. and Okano, H. (2001).
Visualization, direct isolation, and transplantation of midbrain dopaminergic neurons.
Proc Natl Acad Sci U S A 98, 6423-6428.
Sawamoto, K., Winge, P., Koyama, S., Hirota, Y., Yamada, C., Miyao, S., Yoshikawa, S., Jin, M. H., Kikuchi, A., and Okano, H. (1999).
The Drosophila Ral GTPase regulates developmental cell shape changes through the Jun NH(2)-terminal kinase pathway.
J Cell Biol 146, 361-372.
Sawamoto, K., Yamada, C., Kishida, S., Hirota, Y., Taguchi, A., Kikuchi, A., and Okano, H. (1999).
Ectopic expression of constitutively activated Ral GTPase inhibits cell shape changes during Drosophila eye development.
Oncogene 18, 1967-1974.
Sawamoto, K., Taguchi, A., Hirota, Y., Yamada, C., Jin, M. H., and Okano, H. (1998). Argos induces programmed cell death in the developing Drosophila eye by inhibition of the Ras pathway.
Cell Death Differ 5, 262-270.
Sawamoto, K., and Takahashi, N. (1997).
Modulation of hepatocyte function by changing the cell shape in primary culture.
In Vitro Cell Dev Biol Anim 33, 569-574.
Sawamoto, K., Okabe, M., Tanimura, T., Mikoshiba, K., Nishida, Y., and Okano, H. (1996).
The Drosophila secreted protein Argos regulates signal transduction in the Ras/MAPK pathway.
Dev Biol 178, 13-22.
Sawamoto, K., Okabe, M., Tanimura, T., Hayashi, S., Mikoshiba, K., and Okano, H. (1996).
argos Is required for projection of photoreceptor axons during optic lobe development in Drosophila.
Dev Dyn 205, 162-171.
Sawamoto, K., and Okano, H. (1996)
Cell-cell interactions during neural development: multiple types of lateral inhibitions involved in Drosophila eye development.
Neurosci Res 26:205-214.
Sawamoto, K., and Takahashi, N. (1995).
Changes in the organelle arrangement in primary cultured hepatocytes following the formation of cytoskeleton.
Int J Tissue React 17, 205-210.
Sawamoto, K., Okano, H., Kobayakawa, Y., Hayashi, S., Mikoshiba, K., and Tanimura, T. (1994).
The function of argos in regulating cell fate decisions during Drosophila eye and wing vein development.
Dev Biol 164, 267-276.