Research

Molecular and Cellular Neurobiology

Outline

We are studying the cells in the CNS from their birth to death. We aim at elucidation of molecular basis for the control of proliferation, differentiation, and survival of neural precursor cells, hoping that our results will contribute to the treatment of intractable CNS diseases in the near future. We are also studying the interaction between neural cells and vascular cells (especially of cerebral microvessels). Furthermore, we aim at elucidation of molecular basis for the control of neuronal excitation. We welcome anyone who is interested in our work. We also welcome anyone who is interested in the effects of heavy ion irradiation on the central nervous system. Please don’t hesitate to contact us.

Members

Title Name
Professor Yasuki Ishizaki, M.D., Ph.D.
Associate Professor Koji Shibasaki, Ph.D.
Assistant Professor Masashi Kurachi, Ph.D.
Masae Naruse, Ph.D.
Hanako Yamamoto, Ph.D.

Research

Control of survival, proliferation, and differentiation of neural precursor cells
 Even in the presence of saturating amounts of mitogens, cerebellar granule cell precursors (GCPs) exit the cell cycle and differentiate into postmitotic neurons. We have found that p27/Kip1, a cyclin-dependent kinase inhibitor, plays a crucial role in the control of GCP proliferation and differentiation (J. Neurosci. 2000). We are also interested in the plasticity of GCPs. GCPs have long been regarded as being committed to granule cells, but we have got several lines of evidence that these cell can also differentiate into astroglial cells (PNAS 2004). We also showed that CD44-positive cells are candidates for astrocyte precursor cells in developing cerebellum (Cerebellum 2012).

Interaction between neural cells and vascular cells
 We showed that brain microvascular endothelial cell transplantation ameliorates ischemic white matter damage (Brain Res. 2012). We are now studying the molecular basis for this interaction between neural cells and vascular cells.

Control of neuronal excitation by TRP channels
 We are studying control of neuronal excitation by TRP channels using TRPV4 knockout mice. We are also examining the subpopulation of astrocytes which play a role for control of neuronal excitation.

Effects of heavy ion irradiation on neural and vascular cells
 We found that carbon-ion beam irradiation induces ICAM-1 expression via TGF-b1 pathway on vascular endothelial cells (J. Radiat. Res. 2011).

Publications

Sadakata, T., Kakegawa, W., Shinoda, Y., Hosono, M., Katoh-Semba, R., Sekine, Y., Sato, Y., Saruta, C., Ishizaki, Y., Yuzaki, M., Kojima, M., Furuichi, T. Axonal localization of Ca2+-dependent activator protein for secretion 2 is critical for subcellular locality of brain-derived neurotrophic factor and neurotrophin-3 release affecting proper development of postnatal mouse cerebellum. PloS one 9: e99524 (2014).

Akahoshi, N., Kamata, S., Kubota, M., Hishiki, T., Nagahata, Y., Matsuura, T., Yamazaki, C., Yoshida, Y., Yamada, H., Ishizaki, Y., Suematsu, M., Kasahara, T., Ishii, I.: Neutral aminoaciduria in cystathionine b-synthase-deficient mice, a model of homocystinuria, Am. J. Physiol. Renal. Physiol. 306: F1462-1476 (2014).

Shibasaki, K., Ikenaka, K., Tamalu, F., Tominaga, M., Ishizaki, Y.: A novel subtype of astrocytes expressing TRPV4 regulates neuronal excitability via release of gliotransmitters. J. Biol. Chem. (in press, 2014)

Kayakabe, M., Kakizaki, T., Kaneko, R., Sasaki, A., Nakazato, Y., Shibasaki, K., Ishizaki, Y., Saito, H., Suzuki, N., Furuya, N., Yanagawa, Y.: Motor dysfunction in cerebellar Purkinje cell-specific vesicular GABA transporter knockout mice. Front. Cell. Neurosci. 7: 286 (2013)

Shibasaki, K., Ishizaki, Y., Mandadi, S.: Astrocytes functionally express TRPV2 channel. Biochem Biophys Res Commun 441: 327-332, (2013).

Sadakata, T., Kakegawa, W., Shinoda, Y., Hosono, M., Katoh-Semba, R., Sekine, Y., Sato, Y., Tanaka, M., Iwasato, T., Itohara, S., Furuyama, K., Kawaguchi, Y., Ishizaki, Y., Yuzaki,, M. and Furuichi,: T. CAPS1 deficiency perturbs dense-core vesicle trafficking and Golgi structure and reduces presynaptic release probability in the mouse brain. J Neurosci 33: 17326-17334 (2013).

Okano-Uchida,T., Naruse, M., Ikezawa, T., Shibasaki, K., and Ishizaki, Y.: Cerebellar neural stem cells differentiate into two distinct types of astrocytes in response to CNTF and BMP2. Neurosci. Lett. 552: 15-20 (2013).

Naruse, M., Shibasaki, K., Yokoyama, S., Kurachi, M., and Ishizaki, Y.: Dynamic
changes of CD44 expression from progenitors to subpopulations of astrocytes
and neurons in developing cerebellum. PloS one 8: e53109 (2013)

Matsumoto, H., Shibasaki, K., Uchigashima, M., Koizumi, A., Kurachi, M., Moriwaki, Y., Misawa, H., Kawashima, K., Watanabe, M., Kishi, S., Ishizaki, Y.: Localization of acetylcholine-related molecules in the retina: implication of the communication from photoreceptor to retinal pigment epithelium. PloS one 7: e42841 (2012)

Puentes, S., Kurachi, M., Shibasaki, K., Naruse, M., Yoshimoto, Y., Mikuni, M., Imai, H., Ishizaki, Y.: Brain microvascular endothelial cell transplantation ameliorates ischemic white matter damage. Brain Res. 1469: 43-53 (2012).

Cai, N., Kurachi, M., Shibasaki, K., Okano-Uchida, T., Ishizaki, Y.: CD44-positive cells are candidates for astrocyte precursor cells in developing mouse cerebellum. Cerebellum 11: 181-193 (2012).

Akahoshi, N., Ishizaki, Y., Yasuda, H., Murashima, Y. L., Shinba, T., Goto, K., Himi, T., Chun, J., and Ishii, I. : Frequent spontaneous seizures followed by spatial working memory/anxiety deficits in mice lacking sphingosine 1-phosphate receptor 2. Epilepsy & behavior : E&B 10.1016/j.yebeh.2011.09.002 (2011).

Feng, L., Eisenstat, D.D., Chiba, S., Ishizaki, Y., and Shibasaki, K.: Brn-3b inhibits generation of amacrine cells by binding to and negatively regulating DLX1/2 in developing retina. Neuroscience 195:9-20 (2011).

Saito, T., Shibasaki, K., Kurachi, M., Puentes, S., Mikuni, M., Ishizaki, Y.: Cerebral capillary endothelial cells are covered by the VEGF-expressing foot processes of astrocytes. Neurosci. Lett. 497: 116-121 (2011).

Kiyohara, H., Ishizaki, Y., Suzuki, Y., Katoh, H., Hamada, N., Ohno, T., Takahashi, T., Kobayashi, Y., and Nakano, T.: Radiation-induced ICAM-1 expression via TGF-b1 pathway on human umbilical vein endothelial cells; comparison between X-ray and carbon-ion beam irradiation. J. Radiat. Res. 52: 287-292 (2011).

Ibhazehiebo, K., Iwasaki, T., Okano-Uchida, T., Shimokawa, N., Ishizaki, Y., and Koibuchi, N.: Suppression of thyroid hormone receptor-mediated transcription and disruption of thyroid hormone-induced cerebellar morphogenesis by the polybrominated biphenyl mixture, BP-6. NeuroToxicology 32: 400-409 (2011).

Shibasaki, K, Murayama, N, Ono, K, Ishizaki, Y, and Tominaga, M.: TRPV2 enhances axon outgrowth through its activation by membrane stretch in developing sensory and motor neurons. J. Neurosci 30: 4601-4612 (2010).

Akahoshi, N., Kobayashi, C., Ishizaki, Y., Izumi, T., Himi, T., Suematsu, M., and Ishii, I.: Genetic background conversion ameliorates semi-lethality and permits behavioral analyses in cystathionine {beta}-synthase-deficient mice, an animal model for hyperhomocysteinemia. Hum. Mol. Genet. 17: 1994-2005 (2008).

Akahoshi, N., Murashima, Y.L., Himi, T., Ishizaki, Y., and Ishii, I.: Increased expression of the lysosomal protease cathepsin S in hippocampal microglia following kainate-induced seizures. Neurosci. Lett. 429: 136-141 (2007).

Ishizaki, Y.: Control of proliferation and differentiation of neural precursor cells: focusing on the developing cerebellum. J. Pharmacol. Sci. 101: 183-188 (2006).

Okano-Uchida, T., Himi, T., Komiya, Y., and Ishizaki, Y.: Cerebellar granule cell precursors can differentiate into astroglial cells. Proc. Natl. Acad. Sci. USA 101: 1211-1216 (2004).

Himi, T., Ishizaki, Y., and Murota, S.I.: 4,4′-diisothiocyano-2, 2′-stilbenedisulfonate protects cultured cerebellar granule neurons from death. Life Sci. 70: 1235-1249 (2002).

Miyazawa, K., Himi, T., Garcia, V., Yamagishi, H., Sato, S., and Ishizaki, Y.: A role for p27/Kip1 in the control of cerebellar granule cell precursor proliferation. J. Neurosci. 20: 5756-5763 (2000).

Maeno, E., Ishizaki, Y., Kaneseki, T., Hazama, A., and Okada, Y.: Normotonic cell shrinkage because of disordered volume regulation is an early prerequisite to apoptosis. Proc. Natl. Acad. Sci. USA 97: 9487-9492 (2000).

Himi, T., Ishizaki, Y., and Murota, S.: A caspase inhibitor blocks ischemia-induced delayed neuronal death in the gerbil. Eur. J. Neurosci. 10:777-781 (1998).

Ishizaki, Y., Jacobson, M.D., and Raff, M.C.: A role for caspases in lens fiber differentiation. J. Cell Biol. 140:153-158 (1998).

Ishizaki, Y., Cheng, L., Mudge, A.W., and Raff, M.C.: Programmed cell death by default in normal and immortal fibroblasts and in cancer cells. Mol. Biol. Cell 6:1443-1458 (1995).

Ishizaki, Y., Burne, J.F., and Raff, M.C.: Autocrine signals enable chondrocytes to survive in culture. J. Cell Biol. 126:1069-1077 (1994).

Raff, M.C., Barres, B.A., Burne, J.F., Coles, H.S., Ishizaki, Y., and Jacobson, M.D.: Programmed cell death and the control of cell survival: lessons from the nervous system. Science 262:695-700 (1993).

Ishizaki, Y., Voyvodic, J.T., Burne, J.F., and Raff, M.C.: Control of lens epithelial cell survival. J. Cell Biol. 121: 899-908 (1993).