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Research Interests

The human body is composed of hundreds of different cell types that each perform distinct functions but which (except for the germline) all contain the same genetic information. A fundamental question with regard to tissue development is how tissue stem cells or multipotent progenitor cells give rise to various cell types in appropriate numbers and at the right locations to achieve tissue organization. Our laboratory has focused on identifying the mechanisms and logic that underlie the regulation of neural stem-progenitor cell fate both during embryonic brain development and in adulthood.

We are currently investigating genetic and epigenetic regulation of neural stem-progenitor cell fate and neuronal maturation as well as the genesis and maintenance of adult neural stem cells. We are also studying the relevance of these processes to neurodevelopmental disorders.

Ongoing research projects

  1. Investigation of Mechanisms Regulating Neural Stem-Progenitor Cell Fate during Neocortical Development
    • Exploring the roles of chromatin modifiers, such as Polycomb group and HMGA proteins, in regulating the fate of neural stem-progenitor cells during the expansion, neurogenic, and gliogenic phases.
    • Studying the mechanisms that govern fate commitment, differentiation, and reprogramming of specific neuronal and glial cell types.
    • Investigating the factors that determine the identity and size of neocortical areas in mice and humans.
    • Examining both environmental and intrinsic factors that modulate the initial stages of neuronal migration and maturation.
  2. Investigation of Genetic and Epigenetic Regulation of Neuronal Activation
    • Investigating the roles of chromatin modifiers in neuronal activity-dependent processes.
    • Understanding their relevance to learning and memory.
  3. Investigation of the Embryonic Origin of Adult Neural Stem Cells
    • Characterizing the identity and diversity of embryonic precursors ("origin") of adult neural stem cells and comparing them with other embryonic neural progenitor cells involved in brain development.
    • Studying the niche signals responsible for the establishment and maintenance of these precursor cells.
    • Examining the epigenetic modifiers that regulate the differentiation potential of these precursor cells.
  4. Investigation of Dysregulation of Neural Stem-Progenitor Cell and Neuronal Fate in Neurodevelopmental Disorders
    • Examining the effects of early life stresses on the mechanisms related to neocortical development mentioned above.
    • Investigating the relevance of these mechanisms to psychiatric conditions, such as autism spectrum disorder and schizophrenia.
  5. Investigation of Innate Immune Responses in the Brain
    • Studying the basic mechanisms of cellular responses to viral infection in the brain.
    • Examining the effects of maternal immune activation on brain development, specifically on neural stem-progenitor cell fate and microglia, and their relevance to neurodevelopmental disorders.

Selected Publications

Hirata, Y., Kitanishi, Y., Sugishita, H. and Gotoh, Y.
Fast reconstruction of an original continuous series from a recurrence plot.
Chaos 31, 121101. 2021
Harada, Y., Yamada, M., Imayoshi, I., Kageyama, R., Suzuki, Y., Kuniya, T., Furutachi, S., Kawaguchi, D. and Gotoh, Y.
Cell cycle arrest determines adult neural stem cell ontogeny by an embryonic Notch-nonoscillatory Hey1 module.
Nat. Commun. 12, 6562, 2021.
Eto, H., Kishi, Y., Yakushiji-Kaminatsu, N., Sugishita, H., Utsunomiya, S., Koseki, H. and Gotoh, Y.
The Polycomb group protein Ring1 regulates dorsoventral patterning of the mouse telencephalon.
Nat. Comm. 11, 5709, 2020.
Nagahama, K., Sakoori, K., Watanabe, T., Kishi, Y., Kawaji, K., Koebis, M., Nakao, K., Gotoh, Y., Aiba, A., Uesaka, N. and Kano, M.
Setd1a insufficiency in mice attenuates excitatory synaptic function and recapitulates Schizophrenia-related behavioral abnormalities.
Cell Rep. 32 (11):108126, 2020.
Tsuboi, M., Hirabayashi, Y. and Gotoh, Y.
Diverse gene regulatory mechanisms mediated by Polycomb group proteins during neural development.
Curr. Opin. Neurobiol. 59, 164-173, 2019.
Tsuboi, M., Kishi, Y., Kyozuka, W., Koseki, H., Hirabayashi, Y. and Gotoh, Y.
Ubiquitination-Independent Repression of PRC1 Targets during Neuronal Fate Restriction in the Developing Mouse Neocortex.
Dev. Cell 47, 758-772, 2018.
Lanjakornsiripan, D., Pior, BJ., Kawaguchi, D., Furutachi, S., Tahara, T., Katsuyama, Y., Suzuki, Y., Fukazawa, F. and Gotoh, Y.
Layer-specific heterogeneity of astrocytes and its dependence on neuronal layers.
Nat. Comm. 9,1623, 2018.
Itoh, Y., Higuchi, M., Oishi, K.,Kishi, Y., Okazaki, T., Sakai, H., Miyata, T., Nakajima, K., Gotoh, Y.
The PDK1-Akt Pathway Regulates Radial Neuronal Migration and Microtubules in the Developing Mouse Neocortex.
Proc. Natl. Acad. Sci. U.S.A. 113(21) E2955-64, 2016.
Nagao, M., Ogata, T.,Sawada, Y., and Gotoh,Y.
Zbtb20 promotes astrocytogenesis during neocortical development.
Nat. Comm. 7, 11102, 2016.
Furutachi, S., Miya, H., Watanabe, T., Kawai, H., Yamasaki, N., Harada, Y., Imayoshi, I., Nelson, M., Nakayama, KI., Hirabayashi, Y., and Gotoh, Y.
Slowly dividing neural progenitors are an embryonic origin of adult neural stem cells.
Nat. Neurosci. 18, 657-65, 2015.
Okazaki, T., Higuchi, M., Takeda, K., Iwatuki-Horimoto, K., Kiso, M., Miyagishi, M., Yanai, H., Kato, A., Yoneyama, M., Fujita, T., Taniguchi, T., Kawaoka, Y., Ichijo, H. and Gotoh, Y.
The ASK family kinases differentially mediate induction of type I interferon and apoptosis during the antiviral response.
Sci. Signal. 8, ra78. Doi: 10.1126/scisignal.aab1883, 2015.
Morimoto-Suzki, N., Hirabayashi, Y., Tyssowski, K., Singa, J., Vidal, M., Koseki, H. and Gotoh, Y.
The polycomb component Ring1B regulates the timed termination of subcerebral projection neuron production during mouse neocortical development.
Development 141, 4343-4353, 2014.
Nagao, M., Lanjakornsiripan, D., Itoh, Y., Kishi, Y., Ogata, T. and Gotoh, Y.
High mobility group nucleosome-binding family proteins promote astrocyte differentiation of neural precursor cells.
Stem Cells 32, 2983-2997, 2014.
Kawaguchi, D., Furutachi, S., Kawai, H., Hozumi, K. and Gotoh, Y.
Dll1 maintains quiescence of adult neural stem cells and segregates asymmetrically during mitosis.
Nat. Commun. 4, 1880, 2013.
Furutachi, S., Matsumoto, A., Nakayama, K.I. and Gotoh, Y.
p57 controls adult neural stem cell quiescence and modulates the pace of lifelong neurogenesis.
EMBO J. 32, 970-981, 2013.
Itoh, Y., Moriyama, Y., Hasegawa, T., Endo, T.A., Toyoda, T. and Gotoh, Y.
Scratch regulates neuronal migration onset via an epithelial-mesenchymal transition-like mechanims.
Nat. Neurosci. 16, 416-425, 2013.
Kishi, Y., Fujii, Y., Hirabayashi, Y. and Gotoh, Y.
HMGA proteins regulate global chromatin state and the neurogenic potential in neocortical precursor cells.
Nat. Neurosci. 15, 1127-1133, 2012.
Onoguchi, M., Hirabayashi, Y., Koseki, H. and Gotoh, Y.
A noncoding RNA regulates the neurogenin1 gene locus during mouse neocortical development.
Proc. Natl. Acad. Sci. U.S.A. 109, 16939-16944, 2012.
Hirabayashi, Y. and Gotoh, Y.
Epigenetic control of neural precursor cell fate during development.
Nat. Rev. Neurosci., 11, 377-88, 2010.
Kuwahara, A., Hirabayashi, Y., Knoepfler, P.S., Taketo, M.M., Sakai, J., Kodama, T. and Gotoh, Y.
Wnt signaling and its downstream target N-myc regulate basal progenitors in the developing neocortex.
Development 137, 1035-1044, 2010.
Miyata, T., Kawaguchi, D., Kawaguchi, A. and Gotoh, Y.
Mechanisms that regulate the number of neurons during mouse neocortical development.
Curr. Opin. Neurobiol. 20, 22-28, 2010.
Hirabayashi, Y., Suzki, N., Tsuboi, M., Endo, T.A., Toyoda, T., Shinga, J., Koseki, H., Vidal, M. and Gotoh, Y.
Polycomb limits the neurogenic competence of neural precursor cells to promote astrogenic fate transition.
Neuron 63, 600-613, 2009.
Oishi, K., Watatani, K., Itoh, Y., Okano, H., Guillemot, F., Nakajima, K. and Gotoh, Y.
Selective induction of neocortical GABAergic neurons by the PDK1-Akt pathway through activation of Mash1.
Proc. Natl. Acad. Sci. U.S.A. 106, 13064-13069, 2009.
Higuchi, M., Onishi, K., Yoneyama, C. and Gotoh, Y.
Scaffolding function of PAK in the PDK1-Akt pathway.
Nat. Cell Biol. 10, 1356-1364, 2008.
Kawaguchi, D., Yoshimatsu, T., Hozumi, K. and Gotoh, Y.
Selection of differentiating cells by different levels of delta-like 1 among neural precursor cells in the developing mouse telencephalon.
Development 135, 3849-3858, 2008.
Mori, Y., Higuchi, M., Hirabayashi, Y., Fukuda, M. and Gotoh, Y.
JNK phosphorylates Syt 4 and enhances Ca2+-evoked release.
EMBO J. 27, 76-87, 2008.
Ura, S., Nishina, H., Gotoh, Y. and Katada, T.
Activation of the c-Jun N-terminal kinase pathway by MST1 is essential and sufficient for the induction of chromatin condensation during apoptosis.
Mol. Cell Biol. 27, 5514-5522, 2007.
Yoshimatsu, T., Kawaguchi, D., Oishi, K., Takeda, K., Akira, S., Masuyama, N. and Gotoh, Y.
Non-cell-autonomous action of STAT3 in maintenance of neural precursor cells in the mouse neocortex.
Development 133, 2553-2563, 2006.
Sunayama, J., Tsuruta, F., Masuyama, N. and Gotoh, Y.
JNK antagonizes Akt-mediated survival signals by phosphorylating 14-3-3.
J. Cell. Biol. 170, 295-304, 2005.
Kamakura, S., Oishi, K., Yoshimatsu, T., Nakafuku, M., Masuyama, N. and Gotoh, Y.
Hes binding to STAT3 mediates crosstalk between Notch and JAK-STAT signaling.
Nat. Cell Biol. 6, 547-554, 2004.
Tsuruta, F., Sunayama, J., Mori, Y., Shimizu, S., Tsujimoto, Y., Yoshioka, K., Masuyama, N. and Gotoh, Y.
JNK promotes Bax translocation to mitochondria through phosphorylation of 14-3-3 proteins.
EMBO J. 23, 1889-1899, 2004.
Hirabayashi, Y., Itoh, Y., Tabata, H., Nakajima, K., Akiyama, T., Masuyama, N. and Gotoh, Y.
The Wnt-beta-catenin pathway directs neuronal differentiation of cortical neural precursor cells.
Development 131, 2791-2801, 2004.
Ogawara, Y., Kishishita, S., Obata, T., Suzuki, T., Tanaka, K., Masuyama, N. and Gotoh, Y.
Akt enhances Mdm2-mediated ubiquitination and degradation of p53.
J. Biol. Chem. 277, 21843-21850, 2002.
Tsuruta, F., Masuyama, N. and Gotoh, Y.
The PI3K-Akt pathway suppresses Bax translocation to mitochondria.
J. Biol. Chem. 277, 14040-14047, 2002.
Shinohara, M., Terada, Y., Iwamatsu, A., Shinohara, A., Mochizuki, N., Higuchi, M., Gotoh, Y., Ihara, S., Nagata, S., Itoh, H., Fukui, Y. and Jessberger, R.
SWAP-70 is a guanine nucleotide exchange factor that mediates signaling of membrane ruffling.
Nature 416, 759-763, 2002.
Higuchi, M., Masuyama, N., Suzuki, A. and Gotoh, Y.
Akt mediates Rac/Cdc42-Regulated Cell Motility in Growth Factor-Stimulated Cells and in Invasive PTEN-Knockout Cells.
Curr. Biol. 11, 1958-1962, 2001.
Ura, S., Masuyama, N., Graves, J. and Gotoh, Y.
Caspase Cleavage of MST1 Promotes Nuclear Translocation and Chromatin Condensation.
Proc. Natl. Acad. Sci. USA 98, 10148-10153, 2001.
Gotoh, Y. and Cooper, J.A.
Reactive oxygen species and dimerization-induced activation of ASK1 in TNFα signal transduction.
J. Biol. Chem. 273, 17477-17482, 1998.
Datta, S.R., Dudek, H., Tao, X., Masters, S., Fu, H., Gotoh, Y. and Greenberg, M.E.
Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery.
Cell 91, 231-241, 1997.
Takenaka, K., Gotoh, Y. and Nishida, E.
MAP kinase is required for the spindle assembly checkpoint, but dispensable for the normal M phase entry and exit, in Xenopus egg cell cycle extracts.
J. Cell Biol. 136, 1091-1097, 1997.
Fukuda, M., Gotoh, Y. and Nishida, E.
Interaction of MAP kinase with MAP kinase kinase : Its possible role in the control of nucleocytoplasmic transport of MAP kinase.
EMBO J. 16, 1901-1908, 1997.
Ichijo, H., Nishida, E., Irie, K., ten Dijke, P., Saitoh, M., Moriguchi, T., Takagi, M., Matsumoto, K., Miyazono, K. and Gotoh, Y.
Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways.
Science 275, 90-94, 1997.
Gotoh, Y., Masuyama, N., Dell, K., Shirakabe, K. and Nishida, E.
Initiation of Xenopus oocyte maturation by activation of the mitogen-activated protein kinase cascade.
J. Biol. Chem. 270, 25898-25904, 1995.
Fukuda, M., *Gotoh, Y., Tachibana, T., Dell, K., Hattori, S., Yoneda, Y. and Nishida, E.
Induction of neurite outgrowth by MAP kinase in PC12 cells.
Oncogene 11, 239-244, 1995.
Moriguchi, T., Kawasaki, H., Matsuda, S., *Gotoh, Y. and *Nishida, E.
Evidence for multiple activators for stress-activated protein kinases / c-Jun amino-terminal kinases. Existence of novel activators.
J. Biol. Chem. 270, 12969-12972, 1995.
Matsuda, S., Kawasaki, H., Moriguchi, T., *Gotoh, Y. and *Nishida, E.
Activation of protein kinase cascades by osmotic shock.
J. Biol. Chem. 270, 12781-12786, 1995.
Gotoh, Y., Masuyama, N., Suzuki, A., Ueno, N. and Nishida, E.
Involvement of the MAP kinase cascade in Xenopus mesoderm induction.
EMBO J. 14, 2491-2498, 1995.
Shiina, N., Gotoh, Y., Kubomura, J., Iwamatsu, A. & Nishida, E.
Microtubule severing by elongation factor-1α.
Science 266, 282-285, 1994.
Irie, K., Gotoh, Y., Yasher, B.M., Errede, B., Nishida, E. and Matsumoto, K.
Stimulatory effects of yeast and mammalian 14-3-3 proteins on the Raf protein kinase.
Science 265, 1716-1719, 1994.
Gotoh, Y., Matsuda, S., Takenaka, K., Hattori, S., Iwamatsu, A., Ishikawa, M., Kosako, H. & Nishida, E.
Characterization of recombinant Xenopus MAP kinase kinases mutated at potential phosphorylation sites.
Oncogene 9, 1891-1898, 1994.
Kosako, H., Gotoh, Y. & Nishida, E.
Requirement for the MAP kinase kinase/MAP kinase cascade in Xenopus oocyte maturation.
EMBO J. 13, 2131-2138, 1994.
Mizoguchi, T., Gotoh, Y., Nishida, E., Yamaguchi-Shinozaki, K., Hayashida, N., Iwasaki, T., Kamada, H. & Shinozaki, K.
Characterization of two cDNAs that encode MAP kinase homologues in Arabidopsis thaliana and analysis of the possible role of auxin in activating such kinase activities in cultured cells.
Plant J. 5, 111-122, 1994.
Gotoh, Y., Nishida, E., Shimanuki, M., Toda, T., Imai, Y. & Yamamoto, M.
Schizosaccharomyces pombe Spk1 is a tyrosine-phosphorylated protein functionally related to Xenopus mitogen-activated protein kinase.
Mol. Cell. Biol. 13, 6427-6431, 1993.
Nishida, E. & Gotoh, Y.
The MAP kinase cascade is essential for diverse signal tansduction pathways.
Trends Biochem. Sci. 18, 128-131, 1993.
Kosako, H., *Nishida, E. & *Gotoh, Y.
cDNA cloning of MAP kinase kinase reveals kinase cascade pathways in yeasts to vertebrates.
EMBO J. 12, 787-794, 1993.
Matsuda, S., *Gotoh, Y. & *Nishida, E.
Phosphorylation of Xenopus MAP kinase kinase by MAP kinase kinase kinase and MAP kinase.
J. Biol. Chem. 268, 3277-3281, 1993.
Shiina, N., Moriguchi, T., Ohta, K., *Gotoh, Y. & *Nishida, E.
Regulation of a major microtubule-associated protein by MPF and MAP kinase.
EMBO J. 11, 3977-3984, 1992.
Shirakabe, K., *Gotoh, Y. & Nishida, E.
A MAP kinase activating factor in mammalian mitogen-stimulated cells is homologous to Xenopus M phase MAP kinase activator.
J. Biol. Chem. 267, 16685-16690, 1992.
Kosako, H., *Gotoh, Y., Matsuda, S., Ishikawa, M. & *Nishida, E.
Xenopus MAP kinase activator is a serine/threonine/tyrosine kinase activated by threonine phosphorylation.
EMBO J. 11, 2903-2908, 1992.
Matsuda, S., Kosako, H., Takenaka, K., Moriyama, K., Sakai, H., Akiyama, T., *Gotoh, Y. & *Nishida, E.
Xenopus MAP kinase activator: identification and function as a key intermediate in the phosphorylation cascade.
EMBO J. 11, 973-982, 1992.
Gotoh, Y., Moriyama, K., Matsuda, S., Okumura, E., Kishimoto, T., Kawakami, H., Suzuki, K., Yahara, I., Sakai, H. & Nishida, E.
Xenopus M phase MAP kinase: isolation of its cDNA and activation by MPF.
EMBO J. 10, 2661-2668, 1991.
Gotoh, Y., Nishida, E., Matsuda, S., Shiina, N., Kosako, H., Shiokawa, K., Akiyama, T., Ohta, K. & Sakai, H.
In vitro effects on microtubule dynamics of purified Xenopus M phase-activated MAP kinase.
Nature 349, 251-254, 1991.
Gotoh, Y., Nishida, E., Yamashita, T., Hoshi, M., Kawakami, M. & Sakai, H.
MAP kinase activated by nerve growth factor and epidermal growth factor in PC12 cells. Identity with the mitogen-activated MAP kinase of fibroblastic cells.
Eur. J. Biochem. 193, 661-669, 1990.
Graduate School of Pharmaceutical Sciences, The University of Tokyo
Institute of Molecular and Cellular Biosciences, The University of Tokyo
Department of Chemistry and Biotechnology, School of Engineering,
The University of Tokyo
Department of Integrated Biosciences, The Graduate School of Frontier Sciences,
The University of Tokyo
JST-CREST　Basic Reaserch Programs "Elucidation of the Principles of Formation and Function of the Brain Neural Network and Creation of Control Technologies"
JST-CREST　Basic Reaserch Programs "Innovation for Ideal Medical Treatment Based on the Understanding of Maintenance, Change and Breakdown Mechanisms of Homeostasis among Interacting Organ Systems"
IRCN International Research Center for Neurointelligence