Ishii, Seiji



School of Medicine, Department of Anatomy (Shinanomachi)



Academic Degrees 【 Display / hide

  • 博士 (医学), Keio University, Coursework, 2010.03


Papers 【 Display / hide

  • A next-generation iPSC-derived forebrain organoid model of tauopathy with tau fibrils by AAV-mediated gene transfer

    Cell Reports Methods  2022.09

    Research paper (scientific journal), Joint Work, Accepted

  • Primary cilia safeguard cortical neurons in neonatal mouse forebrain from environmental stress-induced dendritic degeneration

    Ishii S., Sasaki T., Mohammad S., Hwang H., Tomy E., Somaa F., Ishibashi N., Okano H., Rakic P., Hashimoto-Torii K., Torii M.

    Proceedings of the National Academy of Sciences of the United States of America (Proceedings of the National Academy of Sciences of the United States of America)  118 ( 1 )  2021.01

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  00278424

     View Summary

    The developing brain is under the risk of exposure to a multitude of environmental stressors. While perinatal exposure to excessive levels of environmental stress is responsible for a wide spectrum of neurological and psychiatric conditions, the developing brain is equipped with intrinsic cell protection, the mechanisms of which remain unknown. Here we show, using neonatal mouse as a model system, that primary cilia, hair-like protrusions from the neuronal cell body, play an essential role in protecting immature neurons from the negative impacts of exposure to environmental stress. More specifically, we found that primary cilia prevent the degeneration of dendritic arbors upon exposure to alcohol and ketamine, two major cell stressors, by activating cilia-localized insulin-like growth factor 1 receptor and downstream Akt signaling. We also found that activation of this pathway inhibits Caspase-3 activation and caspase-mediated cleavage/fragmentation of cytoskeletal proteins in stress-exposed neurons. These results indicate that primary cilia play an integral role in mitigating adverse impacts of environmental stressors such as drugs on perinatal brain development.

  • Dual role of Rbpj in the maintenance of neural progenitor cells and neuronal migration in cortical development

    Son A.I., Mohammad S., Sasaki T., Ishii S., Yamashita S., Hashimoto-Torii K., Torii M.

    Cerebral Cortex (Cerebral Cortex)  30 ( 12 ) 6444 - 6457 2020.12

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  10473211

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    The development of the cerebral cortex is directed by a series of methodically precise events, including progenitor cell proliferation, neural differentiation, and cell positioning. Over the past decade,many studies have demonstrated the critical contributions of Notch signaling in neurogenesis, including that in the developing telencephalon. However, in vivo evidence for the role of Notch signaling in cortical development still remains limited partly due to the redundant functions of four mammalian Notch paralogues and embryonic lethality of the knockout mice. Here, we utilized the conditional deletion and in vivo gene manipulation of Rbpj, a transcription factor that mediates signaling by all four Notch receptors, to overcome these challenges and examined the specific roles of Rbpj in cortical development.We report severe structural abnormalities in the embryonic and postnatal cerebral cortex in Rbpj conditional knockout mice, which provide strong in vivo corroboration of previously reported functions of Notch signaling in neural development. Our results also provide evidence for a novel dual role of Rbpj in cell type-specific regulation of two key developmental events in the cerebral cortex: The maintenance of the undifferentiated state of neural progenitor cells, and the radial and tangential allocation of neurons, possibly through stage-dependent differential regulation of Ngn1.

  • Kcnn2 blockade reverses learning deficits in a mouse model of fetal alcohol spectrum disorders

    Mohammad S., Page S.J., Wang L., Ishii S., Li P., Sasaki T., Basha A., Salzberg A., Quezado Z., Imamura F., Nishi H., Isaka K., Corbin J.G., Liu J.S., Kawasawa Y.I., Torii M., Hashimoto-Torii K.

    Nature Neuroscience (Nature Neuroscience)  23 ( 4 ) 533 - 543 2020.04

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  10976256

     View Summary

    Learning disabilities are hallmarks of congenital conditions caused by prenatal exposure to harmful agents. These include fetal alcohol spectrum disorders (FASDs) with a wide range of cognitive deficiencies, including impaired motor skill development. Although these effects have been well characterized, the molecular effects that bring about these behavioral consequences remain to be determined. We previously found that the acute molecular responses to alcohol in the embryonic brain are stochastic, varying among neural progenitor cells. However, the pathophysiological consequences stemming from these heterogeneous responses remain unknown. Here we show that acute responses to alcohol in progenitor cells altered gene expression in their descendant neurons. Among the altered genes, an increase of the calcium-activated potassium channel Kcnn2 in the motor cortex correlated with motor learning deficits in a mouse model of FASD. Pharmacologic blockade of Kcnn2 improves these learning deficits, suggesting Kcnn2 blockers as a new intervention for learning disabilities in FASD.

  • Rostrocaudal areal patterning of human PSC-derived cortical neurons by FGF8 signaling

    Imaizumi K., Fujimori K., Ishii S., Otomo A., Hosoi Y., Miyajima H., Warita H., Aoki M., Hadano S., Akamatsu W., Okano H.

    eNeuro (eNeuro)  5 ( 2 )  2018.03

    Research paper (scientific journal), Joint Work, Accepted

     View Summary

    The cerebral cortex is subdivided into distinct areas that have particular functions. The rostrocaudal (R-C) gradient of fibroblast growth factor 8 (FGF8) signaling defines this areal identity during neural development. In this study, we recapitulated cortical R-C patterning in human pluripotent stem cell (PSC) cultures. Modulation of FGF8 signaling appropriately regulated the R-C markers, and the patterns of global gene expression resembled those of the corresponding areas of human fetal brains. Furthermore, we demonstrated the utility of this culture system in modeling the area-specific forebrain phenotypes [presumptive upper motor neuron (UMN) phenotypes] of amyotrophic lateral sclerosis (ALS). We anticipate that our culture system will contribute to studies of human neurodevelopment and neurological disease modeling.

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Papers, etc., Registered in KOARA 【 Display / hide

Research Projects of Competitive Funds, etc. 【 Display / hide

  • ヒト前脳型コリン作動性神経細胞の選択的誘導法の開発と、薬剤評価系への応用


    日本医療研究開発機構 (AMED), 再生医療実現拠点ネットワークプログラム 幹細胞・再生医学イノベーション創出プログラム, Research grant, Principal investigator

  • 中枢神経系の発生においてストレス臨界期を制御する一次繊毛の意義と分子機構の解析


    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

  • 大脳皮質形成における環境ストレス応答下流カスケードの解析


    Grant-in-Aid for Scientific Research, Research grant, Principal investigator


Courses Taught 【 Display / hide











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