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Yamaguchi Yoshifumi

Institute of Low Temperature Science　Environmental BiologyProfessor

哺乳類の冬眠に注目し研究を行なっています。哺乳類の冬眠は寒冷や飢餓といった厳しい環境変化に対する動物の適応機構ですが、個体の生き死にの狭間が見れる究極的な現象ともいえ、未開拓の地が残された魅惑的な研究分野です。おもに季節に応じたからだの変化、冬眠の制御に関わる遺伝子の同定、低温耐性といった視点から、幅広く研究を進めています。哺乳類の冬眠研究を行う前は、細胞社会における細胞死の制御とその意義について調べていました。細胞の生き死にの境界を決めるものは何で、死にはどんな意義があるのか、哺乳類の発生過程や炎症応答を中心に見ていました。低温耐性にまつわる研究が、冬眠研究と細胞死研究の境界領域で面白くなってきています。季節に応じたからだの変化は、白色脂肪・褐色脂肪・骨格筋・肝臓・脳下垂体などのリモデリングと臓器連関に着目した研究を進めています。冬眠制御に関わる遺伝子は遺伝学的手法を用いた機能的同定を主眼としつつ、最近は進化的観点も取り入れた研究を進めています。

Researcher basic information

■ Degree
  • Ph.D, 京都大学, Mar. 2005
■ URL
researchmap URLホームページURL■ Various IDs
J-Global ID■ Research Keywords and Fields
Research Keyword
  • hibernation
  • 細胞死
  • 肝臓
  • 脂質代謝
  • 骨格筋
  • ビタミンE
  • マクロファージ
  • 神経管閉鎖
  • 発生生物学
  • カスパーゼ
  • アポトーシス
  • イメージング
  • 時間生物学
Research Field
  • Life Science, Animal physiological chemistry, physiology and behavioral biology, Hibernation
  • Life Science, Medical biochemistry, 細胞死の生物学
  • Life Science, Developmental biology, 哺乳類胚発生
■ Educational Organization

Career

■ Career
Career
  • Apr. 2026 - Present
    Hokkaido University, Institute of Low Temperature Science, Director
  • Apr. 2021 - Present
    InaRIS （稲盛科学財団）フェロー
  • Jan. 2018 - Present
    Hokkaido University, Institute of Low Temperature Science, 教授
  • Jun. 2016 - Dec. 2017
    The University of Tokyo, Graduate School of Pharmaceutical Sciences, 准教授
  • 2007 - Jun. 2016
    The University of Tokyo, Graduate School of Pharmaceutical Sciences, 助教
  • Oct. 2012 - Mar. 2016
    JSTさきがけ・研究員
  • 2006
    東京大学 薬学研究科(研究院), 助手
Position History
  • 低温科学研究所副所長, 2022年4月1日 - 2024年3月31日
  • 低温科学研究所副所長, 2024年4月1日 - 2026年3月31日

Research activity information

■ Papers
  • Type-specific and hibernation-associated skeletal muscle remodeling of the back muscle in Syrian hamsters
    Nanaka Matsuoka; Akari Yamauchi; Yoshifumi Yamaguchi
    The Journal of Physiological Sciences, Nov. 2026
    Scientific journal
  • Effect of post-weaning diet on hibernation occurrence in Syrian hamsters.
    Akari Yamauchi; Sachiyo Enju; Kanako Sone; Nanaka Matsuoka; Yutaka Tamura; Yoshifumi Yamaguchi
    Experimental animals, 10 Mar. 2026, [Domestic magazines]
    English, Scientific journal, Mammalian hibernation is an adaptive strategy for surviving harsh cold seasons and food scarcity by suppressing the metabolic rate and thermogenesis. The Syrian hamster (Mesocricetus auratus) (hereafter termed as hamsters), a small mammalian hibernator, hibernates upon exposure to winter-like, short-photoperiod and cold (SP-Cold) conditions throughout a year in a laboratory, and therefore is a useful animal model obtained from a commercial breeder to study mechanisms of hibernation. However, the rates of hibernation occurrence often vary among experiments and facilities, the reason for which is largely unclear. Here we examined the effects of diet given to hamsters during post-weaning stages on hibernation occurrence. Hamsters fed either a high-nutrient (H) diet suitable for reproduction or a standard (STD) diet during the post-weaning period (from 3 or 4 weeks of age to sexual maturation) were exposed to winter-like conditions, and the occurrence of hibernation was assessed. Females showed a higher hibernation induction rate (over 80%) regardless of the post-weaning diet type than males. Approximately half (52%) of the males fed the STD diet from 3 weeks hibernated, whereas males fed the STD diet from 4 weeks or the H diet showed markedly lower hibernation induction rates (≤33%). These results suggest that female Syrian hamsters are more prone to hibernation than males and that the hibernation induction rate in male hamsters is influenced by diet during a critical developmental window between 3 and 4 weeks of age.
  • Tools of hibernation measurement and interpretation (TOHMIN) for quantifying various values from body temperature fluctuation during hibernation
    Reo Otsuka; Yutaro Shimoyama; Satoshi Nakagawa; Takaoki Kasahara; James F. Staples; Lydia K. Greene; Marina B. Blanco; Yoshifumi Yamaguchi
    Royal Society Open Science, 14 Jan. 2026
    Scientific journal
  • Cold‐Induced Suppression of Myogenesis in Skeletal Muscle Stem Cells Contributes to Delayed Muscle Regeneration During Hibernation
    Tatsuya Miyaji; Ryuichi Kasuya; Mayuko Monden; Yutaka Tamura; Michito Shimozuru; Toshio Tsubota; Daisuke Tsukamoto; Guangyuan Li; Shota Kawano; Yuri Watanabe; Yoshifumi Yamaguchi; Masatomo Watanabe; Mitsunori Miyazaki
    The FASEB Journal, 15 Dec. 2025
    English, Scientific journal, ABSTRACT
    Mammalian hibernators experience profound cold stress and prolonged physical inactivity during torpor periods; however, it is unclear how skeletal muscle stem cells (satellite cells; SCs) respond to these challenges. In this study, we demonstrated that SCs from a mammalian hibernator, the Syrian hamster, exhibit remarkable resistance to cold‐induced cell death, which is associated with intrinsically higher expression of the antioxidant enzyme GPX4, likely contributing to ferroptosis suppression. RNA‐seq analysis revealed widespread downregulation of myogenesis‐related genes following cold exposure, suggesting suppression of the myogenic program. Consistently, SCs exposed to cold stress exhibited reduced activation and differentiation capacity upon subsequent rewarming, with an increased number of quiescent Pax7‐positive/MyoD‐negative cells. Muscle regeneration was markedly delayed during hibernation, accompanied by decreased SC activation and macrophage infiltration, suggesting that cold‐induced suppression of SC function underlies the limited regenerative capacity in hibernating hamsters. Our results provide insights into the unique physiology of mammalian hibernators: SC viability is preserved, whereas regenerative activity is selectively suppressed during hibernation.
  • Identification of genes supporting cold resistance of mammalian cells: lessons from a hibernator.
    Masamitsu Sone; Nonoka Mitsuhashi; Yuki Sugiura; Yuta Matsuoka; Rae Maeda; Akari Yamauchi; Ryoto Okahashi; Junpei Yamashita; Kanako Sone; Sachiyo Enju; Daisuke Anegawa; Yoshifumi Yamaguchi
    Cell death & disease, 15, 9, 685, 685, 19 Sep. 2024, [International Magazine]
    English, Scientific journal, Susceptibility of human cells to cold stress restricts the use of therapeutic hypothermia and long-term preservation of organs at low temperatures. In contrast, cells of mammalian hibernators possess remarkable cold resistance, but little is known about the molecular mechanisms underlying this phenomenon. In this study, we conducted a gain-of-function screening of genes that confer cold resistance to cold-vulnerable human cells using a cDNA library constructed from the Syrian hamster, a mammalian hibernator, and identified Gpx4 as a potent suppressor of cold-induced cell death. Additionally, genetic deletion of or pharmacological inhibition of Gpx4 revealed that Gpx4 is necessary for suppressing lipid peroxidation specifically under cold in hamster cell lines. Genetic disruption of other ferroptosis-suppressing pathways, namely biopterin synthesis and mitochondrial or plasma membrane CoQ reduction pathways, also accelerated cold-induced cell death under Gpx4 dysfunction. Collectively, ferroptosis-suppressing pathways protect the cells of a mammalian hibernator from cold-induced cell death and the augmentation of these pathways renders cold resistance to cells of non-hibernators, including humans.
  • Frequency-modulated timer regulates torpor–arousal cycles during hibernation in distinct small mammalian hibernators
    Shingo Gibo; Yoshifumi Yamaguchi; Elena O. Gracheva; Sviatoslav N. Bagriantsev; Isao T. Tokuda; Gen Kurosawa
    npj Biological Timing and Sleep, 02 Jul. 2024
    English, Scientific journal, AbstractHibernation allows mammals to endure harsh seasons by reducing their basal metabolism and body temperature (Tb) to minimize energy expenditure. During hibernation in small animals such as Syrian hamsters and 13-lined ground squirrels, Tb decreases to an ambient level ( < 5 °C) and remains constant for days to weeks in a physiological condition termed deep torpor. Torpor is interrupted by periods of arousal, during which Tb recovers to a euthermic level (approximately 37 °C), and these torpor–arousal cycles are repeated multiple times during hibernation. However, little is known about the mechanisms governing Tb fluctuations during hibernation. In this study, we employed an unbiased model selection approach to Tb data and revealed that a model incorporating frequency modulation quantitatively reproduced Tb fluctuation during hibernation in Syrian hamsters. We found that an unexpectedly long period of 120–430 days modulates a shorter period of several days. In addition, the aforementioned model reproduced Tb fluctuation in 13-lined ground squirrels, which can undergo repeated hibernation according to intrinsic circannual rhythms in constant laboratory conditions. This is the first quantitative study to demonstrate the concerted action of two endogenous periods, one lasting a few days and the other lasting a year, in the torpor–arousal cycles of distinct mammalian hibernators. We anticipate that our theoretical analysis of Tb fluctuation will be a starting point for quantitative comparisons of hibernation patterns across various hibernating species. Furthermore, quantification of Tb data using models will foster our understanding of the molecular mechanisms of hibernation by revealing the biological processes operating within these periods.
  • 冬眠哺乳類シリアンハムスターの脂質代謝関連臓器におけるオミクス解析
    山内 彩加林; 山下 純平; 杉浦 悠毅; 松岡 悠太; 曽根 正光; 山口 良文
    脂質生化学研究, 66, 43, 46, 日本脂質生化学会, May 2024
    Japanese
  • Slow decrease in temperature produces readthrough transcripts in mammalian hibernation
    Masamitsu Sone; Junpei Yamashita; Shuji Shigenobu; Yoshifumi Yamaguchi
    Biochemical and Biophysical Research Communications, 709, 149837, 149837, Elsevier BV, May 2024, [Peer-reviewed], [Corresponding author]
    Scientific journal
  • Nail growth arrest under low body temperature during hibernation
    Taiga Ishimoto; Hideyuki Kosumi; Ken Natsuga; Yoshifumi Yamaguchi
    The Journal of Physiological Sciences, 27 Apr. 2024, [Peer-reviewed], [Corresponding author]
    Scientific journal
  • Cold resistance of mammalian hibernators ∼ a matter of ferroptosis?
    Masamitsu Sone; Yoshifumi Yamaguchi
    Frontiers in Physiology, 25 Apr. 2024, [Peer-reviewed]
    Scientific journal, Most mammals adapt thermal physiology around 37°C and large deviations from their range, as observed in severe hypothermia and hyperthermia, resulting in organ dysfunction and individual death. A prominent exception is mammalian hibernation. Mammalian hibernators resist the long-term duration of severe low body temperature that is lethal to non-hibernators, including humans and mice. This cold resistance is supported, at least in part, by intrinsic cellular properties, since primary or immortalized cells from several hibernator species can survive longer than those from non-hibernators when cultured at cold temperatures. Recent studies have suggested that cold-induced cell death fulfills the hallmarks of ferroptosis, a type of necrotic cell death that accompanies extensive lipid peroxidation by iron-ion-mediated reactions. In this review, we summarize the current knowledge of cold resistance of mammalian hibernators at the cellular and molecular levels to organ and systemic levels and discuss key pathways that confer cold resistance in mammals.
  • Cold-induced suspension and resetting of Ca2+ and transcriptional rhythms in the suprachiasmatic nucleus neurons
    Ryosuke Enoki; Naohiro Kon; Kimiko Shimizu; Kenta Kobayashi; Sota Hiro; Ching-Pu Chang; Tatsuto Nakane; Hirokazu Ishii; Joe Sakamoto; Yoshifumi Yamaguchi; Tomomi Nemoto
    iScience, Dec. 2023, [Peer-reviewed]
    English, Scientific journal
  • Spontaneous recurrence of a summer-like diel rhythm in the body temperature of the Syrian hamster after hibernation
    Satoshi Nakagawa; Yoshifumi Yamaguchi
    Proceedings of the Royal Society B: Biological Sciences, 25 Oct. 2023, [Peer-reviewed], [Corresponding author]
    Scientific journal
  • How do cells of mammalian hibernators cope with cold stress?
    Masamitsu Sone; Yoshifumi Yamaguchi
    Low Temperature Science, 81, 159, 172, 20 Mar. 2023, [Peer-reviewed], [Invited]
    Japanese, Scientific journal
  • Generation of transgenic mice expressing a FRET biosensor, SMART, that responds to necroptosis
    Shin Murai; Kanako Takakura; Kenta Sumiyama; Kenta Moriwaki; Kenta Terai; Sachiko Komazawa-Sakon; Takao Seki; Yoshifumi Yamaguchi; Tetuo Mikami; Kimi Araki; Masaki Ohmuraya; Michiyuki Matsuda; Hiroyasu Nakano
    Communications Biology, 5, 1, Springer Science and Business Media LLC, 05 Dec. 2022
    Scientific journal, Abstract

    Necroptosis is a regulated form of cell death involved in various pathological conditions, including ischemic reperfusion injuries, virus infections, and drug-induced tissue injuries. However, it is not fully understood when and where necroptosis occurs in vivo. We previously generated a Forster resonance energy transfer (FRET) biosensor, termed SMART (the sensor for MLKL activation by RIPK3 based on FRET), which monitors conformational changes of MLKL along with progression of necroptosis in human and murine cell lines in vitro. Here, we generate transgenic (Tg) mice that express the SMART biosensor in various tissues. The FRET ratio is increased in necroptosis, but not apoptosis or pyroptosis, in primary cells. Moreover, the FRET signals are elevated in renal tubular cells of cisplatin-treated SMART Tg mice compared to untreated SMART Tg mice. Together, SMART Tg mice may provide a valuable tool for monitoring necroptosis in different types of cells in vitro and in vivo.
  • Cold-induced Suspension and Resetting of Ca2+ and Transcriptional Rhythms in the Suprachiasmatic Nucleus Neurons
    Ryosuke Enoki; Naohiro Kon; Kimiko Shimizu; Kenta Kobayashi; Yoshifumi Yamaguchi; Tomomi Nemoto
    Biorxiv, 28, 2, 19 Sep. 2022
  • Step‐by‐step protocols for non‐viral derivation of transgene‐free induced pluripotent stem cells from somatic fibroblasts of multiple mammalian species
    Sho Yoshimatsu; Atsushi Yamazaki; Kazuya Edamura; Yuko Koushige; Hisashi Shibuya; Emi Qian; Tsukika Sato; Junko Okahara; Noriyuki Kishi; Toshiaki Noce; Yoshifumi Yamaguchi; Hideyuki Okano
    Development, Growth & Differentiation, Wiley, 16 Jul. 2022
    Scientific journal
  • A FRET biosensor, SMART, monitors necroptosis in renal tubular epithelial cells in a cisplatin-induced kidney injury model
    Shin Murai; Kanako Takakura; Kenta Sumiyama; Kenta Moriwaki; Kenta Terai; Sachiko Komazawa-Sakon; Yoshifumi Yamaguchi; Tetuo Mikami; Kimi Araki; Masaki Ohmuraya; Michiyuki Matsuda; Hiroyasu Nakano
    Cold Spring Harbor Laboratory, 19 Jun. 2022
    Abstract

    Necroptosis is a regulated form of cell death involved in various pathological conditions, including ischemic reperfusion injuries, virus infections, and drug-induced tissue injuries. However, it is not fully understood when and where necroptosis occurs in vivo. We previously generated a Forster resonance energy transfer (FRET) biosensor, termed SMART (the sensor for MLKL activation based on FRET), which specifically monitored necroptosis in human and murine cell lines in vitro. Here, we generated transgenic (Tg) mice that expressed the SMART biosensor in various tissues. SMART monitored necroptosis, but not apoptosis or pyroptosis, in primary cells, including peritoneal macrophages and embryonic fibroblasts. Moreover, the FRET signal was elevated in renal tubular cells of cisplatin-treated SMART Tg mice compared to untreated SMART Tg mice. Together, SMART Tg mice may provide a valuable tool for monitoring necroptosis in different types of cells in vitro and in vivo.
  • 哺乳類の冬眠〜寒冷と飢餓を乗り切る低代謝・低体温戦略
    中川 哲; 山口 良文
    日本生気象学会雑誌, 58, 3-4, 51, 56, 2022, [Peer-reviewed], [Invited], [Last author, Corresponding author]
    Japanese, Scientific journal
  • Caspase-3 regulates ureteric branching in mice via cell migration.
    Midori Awazu; Yoshifumi Yamaguchi; Michio Nagata; Masayuki Miura; Mariko Hida
    Biochemical and biophysical research communications, 559, 28, 34, 25 Jun. 2021, [Peer-reviewed], [International Magazine]
    English, Scientific journal, Inhibition of caspase-3 (Casp3) reduces ureteric branching in organ culture but the mechanism remains unclear. Since Casp3 has non-apoptotic functions, we examined whether Casp3 regulates ureteric branching by promoting cell migration, using a ureteric bud (UB) cell line and Casp3-deficient (Casp3-/-) mice. Also, we examined whether Casp3 plays a role in the reduced ureteric branching of metanephroi from nutrient restricted mothers, in which Casp3 activity is suppressed. A Casp3 inhibitor Ac-DNLD-CHO reduced FGF2-induced cord formation of UB cells in 3D culture. UB cell migration assessed by Boyden chamber and wound healing assays was inhibited by Ac-DNLD-CHO. Glomerular number was reduced by ≈ 30%, and ureteric tip number was lower in Casp3-/- mice compared with controls. Maternal nutrient restriction decreased ureteric tip number in controls but not in Casp3-/-. In conclusion, Casp3 regulates ureteric branching by promoting UB cell migration. Inhibited ureteric branching by maternal nutrient restriction may be mediated by Casp3.
  • Hepatic resistance to cold ferroptosis in a mammalian hibernator Syrian hamster depends on effective storage of diet-derived α-tocopherol.
    Daisuke Anegawa; Yuki Sugiura; Yuta Matsuoka; Masamitsu Sone; Mototada Shichiri; Reo Otsuka; Noriko Ishida; Ken-Ichi Yamada; Makoto Suematsu; Masayuki Miura; Yoshifumi Yamaguchi
    Communications biology, 4, 1, 796, 796, 25 Jun. 2021, [Peer-reviewed], [International Magazine]
    English, Scientific journal, Mammalian hibernators endure severe and prolonged hypothermia that is lethal to non-hibernators, including humans and mice. The mechanisms responsible for the cold resistance remain poorly understood. Here, we found that hepatocytes from a mammalian hibernator, the Syrian hamster, exhibited remarkable resistance to prolonged cold culture, whereas murine hepatocytes underwent cold-induced cell death that fulfills the hallmarks of ferroptosis such as necrotic morphology, lipid peroxidation and prevention by an iron chelator. Unexpectedly, hepatocytes from Syrian hamsters exerted resistance to cold- and drug-induced ferroptosis in a diet-dependent manner, with the aid of their superior ability to retain dietary α-tocopherol (αT), a vitamin E analog, in the liver and blood compared with those of mice. The liver phospholipid composition is less susceptible to peroxidation in Syrian hamsters than in mice. Altogether, the cold resistance of the hibernator's liver is established by the ability to utilize αT effectively to prevent lipid peroxidation and ferroptosis.
  • Evidence for the involvement of caspases in establishing proper cerebrospinal fluid hydrodynamics.
    Ayako Yoshida; Daisuke Kawata; Naomi Shinotsuka; Mariko Yoshida; Yoshifumi Yamaguchi; Masayuki Miura
    Neuroscience research, 06 Jan. 2021, [Peer-reviewed], [International Magazine]
    English, Scientific journal, A large number of cells undergo apoptosis via caspase activation during and after neural tube closure (NTC) in mammals. Apoptosis is executed by either intrinsic or extrinsic apoptotic pathways, and inhibition of each pathway causes developmental defects around NTC stages, which hampers the physiological roles of apoptosis and caspases after NTC. We generated transgenic mice in which a broad spectrum of caspases could be suppressed in a spatiotemporal manner by pan-caspase inhibitor protein p35 originating from baculovirus. Mice with nervous system-specific expression of p35 (Nestin-Cre (NCre);p35V mice) exhibited postnatal lethality within 1 month after birth. They were born at the expected Mendelian ratio, but demonstrated severe postnatal growth retardation and hydrocephalus. The flow of cerebrospinal fluid (CSF) between the third and fourth ventricles was disturbed, whereas neither stenosis nor abnormality in ciliary morphology was observed in the pathway of CSF flow. Hydrocephalus and growth retardation of NCre;p35V mice were not rescued by the deletion of RIPK3, an essential factor for necroptosis which occurs in the absence of caspase-8 activation during development. The CSF of NCre;p35V mice contained a larger amount of secreted proteins than that of the controls. These findings suggest that the establishment of proper CSF dynamics requires caspase activity during brain development after NTC.
  • Apoptosis is involved in maintaining the character of the midbrain and the diencephalon roof plate after neural tube closure.
    Yudai Matsumoto; Yoshifumi Yamaguchi; Misato Hamachi; Keiko Nonomura; Yukiko Muramatsu; Hiroki Yoshida; Masayuki Miura
    Developmental biology, 468, 1-2, 101, 109, 01 Dec. 2020, [Peer-reviewed], [International Magazine]
    English, Scientific journal, Apoptosis, a major form of programmed cell death, is massively observed in neural plate border and subsequently in the roof plate (RP). While deficiency of apoptosis often results in brain malformations including exencephaly and hydrocephalus, the impact of apoptosis on RP formation and maintenance remains unclear. Here we described that mouse embryos deficient in Apaf1, a gene crucial for the intrinsic apoptotic pathway, in C57BL/6 genetic background exhibited narrow and discontinuous expression of RP marker genes in the midline of the midbrain and the diencephalon. Instead, cells positive for the neuroectodermal gene SOX1 ectopically accumulated in the midline. A lineage-tracing experiment suggests that these ectopic SOX1-positive cells began to accumulate in the midline of apoptosis-deficient embryos after E9.5. These embryos further displayed malformation of the subcommissural organ, which has been discussed in the etiology of hydrocephalus. Thus, the apoptosis machinery prevents ectopic emergence of SOX1-positive cells in the midbrain and the diencephalon RP, and helps in maintaining the character of the RP in the diencephalon and midbrain, thereby ensuring proper brain development.
  • In vivo detection of programmed cell death during mouse heart development
    Kristel Martínez-Lagunas; Yoshifumi Yamaguchi; Cora Becker; Caroline Geisen; Marco C. DeRuiter; Masayuki Miura; Bernd K. Fleischmann; Michael Hesse
    Cell Death & Differentiation, 27, 4, 1398, 1414, Springer Science and Business Media {LLC}, 30 Apr. 2020, [Peer-reviewed]
    Scientific journal
  • A Fluorescent Probe for Rapid, High-Contrast Visualization of Folate-Receptor-Expressing Tumors In Vivo.
    Koji Numasawa; Kenjiro Hanaoka; Naoko Saito; Yoshifumi Yamaguchi; Takayuki Ikeno; Honami Echizen; Masahiro Yasunaga; Toru Komatsu; Tasuku Ueno; Masayuki Miura; Tetsuo Nagano; Yasuteru Urano
    Angewandte Chemie (International ed. in English), 59, 15, 6015, 6020, 06 Apr. 2020, [Peer-reviewed], [International Magazine]
    English, Scientific journal, Folate receptors (FRs) are membrane proteins involved in folic acid uptake, and the alpha isoform (FR-α) is overexpressed in ovarian and endometrial cancer cells. For fluorescence imaging of FRs in vivo, the near-infrared (NIR) region (650-900 nm), in which tissue penetration is high and autofluorescence is low, is optimal, but existing NIR fluorescent probes targeting FR-α show high non-specific tissue adsorption, and require prolonged washout to visualize tumors. We have designed and synthesized a new NIR fluorescent probe, FolateSiR-1, utilizing a Si-rhodamine fluorophore having a carboxy group at the benzene moiety, coupled to a folate ligand moiety through a negatively charged tripeptide linker. This probe exhibits very low background fluorescence and afforded a tumor-to-background ratio (TBR) of up to 83 in FR-expressing tumor-bearing mice within 30 min. Thus, FolateSiR-1 has the potential to contribute to the research in the field of biology and the clinical medicine.
  • Addendum: A FRET biosensor for necroptosis uncovers two different modes of the release of DAMPs
    Shin Murai; Yoshifumi Yamaguchi; Yoshitaka Shirasaki; Mai Yamagishi; Ryodai Shindo; Joanne M. Hildebrand; Ryosuke Miura; Osamu Nakabayashi; Mamoru Totsuka; Taichiro Tomida; Satomi Adachi-Akahane; Sotaro Uemura; John Silke; Hideo Yagita; Masayuki Miura; Hiroyasu Nakano
    Nature Communications, 10, 1, 1923, Springer Science and Business Media LLC, Dec. 2019, [Peer-reviewed]
    Scientific journal
  • Caspase-1 initiates apoptosis in the absence of gasdermin D
    Kohsuke Tsuchiya; Shinsuke Nakajima; Shoko Hosojima; Dinh Thi Nguyen; Tsuyoshi Hattori; Thuong Manh Le; Osamu Hori; Mamunur Rashid Mahib; Yoshifumi Yamaguchi; Masayuki Miura; Takeshi Kinoshita; Hiroko Kushiyama; Mayumi Sakurai; Toshihiko Shiroishi; Takashi Suda
    Nature Communications, 10, 1, 2091, Springer Science and Business Media {LLC}, Dec. 2019, [Peer-reviewed]
    Scientific journal
  • Temporal regulation of Lin28a during mammalian neurulation contributes to neonatal body size control.
    Hidenobu Miyazawa; Yukiko Muramatsu; Hatsune Makino; Yoshifumi Yamaguchi; Masayuki Miura
    Developmental dynamics : an official publication of the American Association of Anatomists, 248, 10, 931, 941, Oct. 2019, [Peer-reviewed], [International Magazine]
    English, BACKGROUND: The timing of developmental events is tightly regulated along a time axis for normal development. Although the RNA-binding protein Lin28a plays a crucial role in the regulation of developmental timing in Caenorhabditis elegans, how the timing of Lin28a expression affects the rate and/or duration of developmental events during mammalian development remains to be addressed. RESULTS: In this study, we discovered that the timing and the duration of Lin28a expression affect embryonic growth. During the neurulation stage of mouse development, endogenous Lin28a levels start to drop. When Lin28a expression was maintained transiently using the inducible tetracycline-regulated gene expression (Tet-ON) system [doxycycline (Dox)-inducible Lin28a transgenic (iLin28a Tg) mice] with Dox administration at E8.5 and E9.5, it resulted in neonatal lethality, increased body weight (organomegaly), and an increased number of caudal vertebrae at birth. On the other hand, Lin28a induction only at E8.5 caused neonatal lethality and organomegaly, but did not affect the caudal vertebra number. Of note, although Dox treatment before or after neurulation still caused neonatal lethality, it neither caused organomegaly nor the increased caudal vertebra number in iLin28a Tg neonates. CONCLUSIONS: Temporal regulation of Lin28a expression during neurulation affects developmental events such as cessation of axial elongation and embryonic growth in mice.
  • Loss of the small GTPase Arl8b results in abnormal development of the roof plate in mouse embryos.
    Keisuke Hashimoto; Yoshifumi Yamaguchi; Yusuke Kishi; Yorifumi Kikko; Kanako Takasaki; Yurie Maeda; Yudai Matsumoto; Miho Oka; Masayuki Miura; Shinya Ohata; Toshiaki Katada; Kenji Kontani
    Genes to cells : devoted to molecular & cellular mechanisms, 24, 6, 436, 448, Jun. 2019, [Peer-reviewed], [International Magazine]
    English, Lysosomes are acidic organelles responsible for degrading both exogenous and endogenous materials. The small GTPase Arl8 localizes primarily to lysosomes and is involved in lysosomal function. In the present study, using Arl8b gene-trapped mutant (Arl8b-/- ) mice, we show that Arl8b is required for the development of dorsal structures of the neural tube, including the thalamus and hippocampus. In embryonic day (E) 10.5 Arl8b-/- embryos, Sox1 (a neuroepithelium marker) was ectopically expressed in the roof plate, whereas the expression of Gdf7 and Msx1 (roof plate markers) was reduced in the dorsal midline of the midbrain. Ectopic expression of Sox1 in Arl8b-/- embryos was detected also at E9.0 in the neural fold, which gives rise to the roof plate. In addition, the levels of Bmp receptor IA and phosphorylated Smad 1/5/8 (downstream of BMP signaling) were increased in the neural fold of E9.0 Arl8b-/- embryos. These results suggest that Arl8b is involved in the development of the neural fold and the subsequently formed roof plate, possibly via control of BMP signaling.
  • A20 prevents inflammasome-dependent arthritis by inhibiting macrophage necroptosis through its ZnF7 ubiquitin-binding domain.
    Polykratis A; Martens A; Eren RO; Shirasaki Y; Yamagishi M; Yamaguchi Y; Uemura S; Miura M; Holzmann B; Kollias G; Armaka M; van Loo G; Pasparakis M
    Nature cell biology, 21, 6, 731, 742, May 2019, [Peer-reviewed], [International Magazine]
    English, Scientific journal, Deficiency in the deubiquitinating enzyme A20 causes severe inflammation in mice, and impaired A20 function is associated with human inflammatory diseases. A20 has been implicated in negatively regulating NF-κB signalling, cell death and inflammasome activation; however, the mechanisms by which A20 inhibits inflammation in vivo remain poorly understood. Genetic studies in mice revealed that its deubiquitinase activity is not essential for A20 anti-inflammatory function. Here we show that A20 prevents inflammasome-dependent arthritis by inhibiting macrophage necroptosis and that this function depends on its zinc finger 7 (ZnF7). We provide genetic evidence that RIPK1 kinase-dependent, RIPK3-MLKL-mediated necroptosis drives inflammasome activation in A20-deficient macrophages and causes inflammatory arthritis in mice. Single-cell imaging revealed that RIPK3-dependent death caused inflammasome-dependent IL-1β release from lipopolysaccharide-stimulated A20-deficient macrophages. Importantly, mutation of the A20 ZnF7 ubiquitin binding domain caused arthritis in mice, arguing that ZnF7-dependent inhibition of necroptosis is critical for A20 anti-inflammatory function in vivo.
  • Development of novel methods that monitor necroptosis and the release of DAMPs at the single cell resolution
    Hiroyasu Nakano; Shin Murai; Yoshifumi Yamaguchi; Yoshitaka Shirasaki; Osamu Nakabayashi; Soh Yamazaki
    Cell Stress, 3, 2, 66, 69, Shared Science Publishers OG, 11 Feb. 2019, [Peer-reviewed]
    Scientific journal
  • A FRET biosensor for necroptosis uncovers two different modes of the release of DAMPs
    Shin Murai; Yoshifumi Yamaguchi; Yoshitaka Shirasaki; Mai Yamagishi; Ryodai Shindo; Joanne M. Hildebrand; Ryosuke Miura; Osamu Nakabayashi; Mamoru Totsuka; Taichiro Tomida; Satomi Adachi-Akahane; Sotaro Uemura; John Silke; Hideo Yagita; Masayuki Miura; Hiroyasu Nakano
    Nature Communications, 9, 1, 4457, Springer Science and Business Media LLC, Dec. 2018, [Peer-reviewed]
    Scientific journal
  • Mammalian embryos show metabolic plasticity toward the surrounding environment during neural tube closure.
    Hidenobu Miyazawa; Masamichi Yamamoto; Yoshifumi Yamaguchi; Masayuki Miura
    Genes to cells : devoted to molecular & cellular mechanisms, 23, 9, 794, 802, Wiley, Sep. 2018, [Peer-reviewed], [International Magazine]
    English, Scientific journal, Developing embryos rewire energy metabolism for developmental processes. However, little is known about how metabolic rewiring is coupled with development in a spatiotemporal manner. Here, we show that mammalian embryos display plasticity of glucose metabolism in response to the extracellular environment at the neural tube closure (NTC) stage, when the intrauterine environment changes upon placentation. To study how embryos modulate their metabolic state upon environmental change, we analyzed the steady-state level of ATP upon exposure to extrauterine environments using both an enzymatic assay and a genetically encoded ATP sensor. Upon environmental changes, NTC-stage embryos exhibited increased ATP content, whereas embryos before and after NTC did not. The increased ATP in the NTC-stage embryos seemed to depend on glycolysis. Intriguingly, an increase in mitochondrial membrane potential (ΔΨm) was also observed in the neural ectoderm (NE) and the neural plate border of the non-neural ectoderm (NNE) region. This implies that glycolysis can be coupled with the TCA cycle in the NE and the neural plate border depending on environmental context. Disrupting ΔΨm inhibited folding of the cranial neural plate. Thus, we propose that embryos tune metabolic plasticity to enable coupling of glucose metabolism with the extracellular environment at the NTC stage.
  • Caspases and matrix metalloproteases facilitate collective behavior of non-neural ectoderm after hindbrain neuropore closure.
    Naomi Shinotsuka; Yoshifumi Yamaguchi; Kenichi Nakazato; Yudai Matsumoto; Atsushi Mochizuki; Masayuki Miura
    BMC developmental biology, 18, 1, 17, 17, 31 Jul. 2018, [Peer-reviewed], [International Magazine]
    English, Scientific journal, BACKGROUND: Mammalian brain is formed through neural tube closure (NTC), wherein both ridges of opposing neural folds are fused in the midline and remodeled in the roof plate of the neural tube and overlying non-neural ectodermal layer. Apoptosis is widely observed from the beginning of NTC at the neural ridges and is crucial for the proper progression of NTC, but its role after the closure remains less clear. RESULTS: Here, we conducted live-imaging analysis of the mid-hindbrain neuropore (MHNP) closure and revealed unexpected collective behavior of cells surrounding the MHNP. The cells first gathered to the closing point and subsequently relocated as if they were released from the point. Inhibition of caspases or matrix metalloproteases with chemical inhibitors impaired the cell relocation. CONCLUSIONS: These lines of evidence suggest that apoptosis-mediated degradation of extracellular matrix might facilitate the final process of neuropore closure.
  • Molecular Basis of White Adipose Tissue Remodeling That Precedes and Coincides With Hibernation in the Syrian Hamster, a Food-Storing Hibernator.
    Yoshifumi Yamaguchi
    Frontiers in physiology, in press, 1973, 01 Jan. 2018, [Peer-reviewed]
    English, Scientific journal, Mammalian hibernators store fat extensively in white adipose tissues (WATs) during pre-hibernation period (Pre-HIB) to prepare for hibernation. However, the molecular mechanisms underlying the pre-hibernation remodeling of WAT have not been fully elucidated. Syrian hamsters, a food-storing hibernator, can hibernate when exposed to a winter-like short day photoperiod and cold ambient temperature (SD-Cold). Animals subjected to prolonged SD-Cold had smaller white adipocytes and beige-like cells within subcutaneous inguinal WAT (iWAT). Time-course analysis of gene expression with RNA-sequencing and quantitative PCR demonstrated that the mRNA expression of not only genes involved in lipid catabolism (lipolysis and beta-oxidation) but also lipid anabolism (lipogenesis and lipid desaturation) was simultaneously up-regulated prior to hibernation onset in the animals. The enhanced capacity of both lipid catabolism and lipid anabolism during hibernation period (HIB) is striking contrast to previous observations in fat-storing hibernators that only enhance catabolism during HIB. The mRNA expression of mTORC1 and PPAR signaling molecules increased, and pharmacological activation of PPARs indeed up-regulated lipid metabolism genes in iWAT explants from Syrian hamsters. These results suggest that the Syrian hamster rewires lipid metabolisms while preparing for hibernation to effectively utilize body fat and synthesize it from food intake during HIB.
  • Arl8b is required for lysosomal degradation of maternal proteins in the visceral yolk sac endoderm of mouse embryos
    Miho Oka; Keisuke Hashimoto; Yoshifumi Yamaguchi; Shin-ichiro Saitoh; Yuki Sugiura; Yuji Motoi; Kurara Honda; Yorifumi Kikko; Shinya Ohata; Makoto Suematsu; Masayuki Miura; Kensuke Miyake; Toshiaki Katada; Kenji Kontani
    JOURNAL OF CELL SCIENCE, 130, 20, 3568, 3577, Oct. 2017, [Peer-reviewed]
    English, Scientific journal
  • Neural tube closure and embryonic metabolism
    Yoshifumi Yamaguchi; Hidenobu Miyazawa; Masayuki Miura
    CONGENITAL ANOMALIES, 57, 5, 134, 137, Sep. 2017, [Peer-reviewed]
    English
  • Rewiring of embryonic glucose metabolism via suppression of PFK-1 and aldolase during mouse chorioallantoic branching
    Hidenobu Miyazawa; Yoshifumi Yamaguchi; Yuki Sugiura; Kurara Honda; Koki Kondo; Fumio Matsuda; Takehiro Yamamoto; Makoto Suematsu; Masayuki Miura
    DEVELOPMENT, 144, 1, 63, 73, Jan. 2017, [Peer-reviewed]
    English, Scientific journal
  • Detection of LacZ-Positive Cells in Living Tissue with Single-Cell Resolution
    Tomohiro Doura; Mako Kamiya; Fumiaki Obata; Yoshifumi Yamaguchi; Takeshi Y. Hiyama; Takashi Matsuda; Akiyoshi Fukamizu; Masaharu Noda; Masayuki Miura; Yasuteru Urano
    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 55, 33, 9620, 9624, Aug. 2016, [Peer-reviewed]
    English, Scientific journal
  • HIF-1 alpha-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity
    Hiroaki Semba; Norihiko Takeda; Takayuki Isagawa; Yuki Sugiura; Kurara Honda; Masaki Wake; Hidenobu Miyazawa; Yoshifumi Yamaguchi; Masayuki Miura; Dana M. R. Jenkins; Hyunsung Choi; Jung-whan Kim; Masataka Asagiri; Andrew S. Cowburn; Hajime Abe; Katsura Soma; Katsuhiro Koyama; Manami Katoh; Keimon Sayama; Nobuhito Goda; Randall S. Johnson; Ichiro Manabe; Ryozo Nagai; Issei Komuro
    NATURE COMMUNICATIONS, 7, 11635, May 2016, [Peer-reviewed]
    English, Scientific journal
  • Decreases in body temperature and body mass constitute pre-hibernation remodelling in the Syrian golden hamster, a facultative mammalian hibernator
    Yuichi Chayama; Lisa Ando; Yutaka Tamura; Masayuki Miura; Yoshifumi Yamaguchi
    ROYAL SOCIETY OPEN SCIENCE, 3, 4, 160002, Apr. 2016, [Peer-reviewed]
    English, Scientific journal
  • Programmed Cell Death in Neurodevelopment
    Yoshifumi Yamaguchi; Masayuki Miura
    DEVELOPMENTAL CELL, 32, 4, 478, 490, Feb. 2015, [Peer-reviewed]
    English
  • Programmed Cell Death and Caspase Functions During Neural Development
    Yoshifumi Yamaguchi; Masayuki Miura
    APOPTOSIS AND DEVELOPMENT, 114, 159, 184, 2015, [Peer-reviewed]
    English, In book
  • Contribution of apoptosis in cranial neural tube closure indicated by mouse embryo live imaging
    Yoshifumi Yamaguchi; Naomi Shinotsuka; Keiko Nonomura; Masayuki Miura
    New Principles in Developmental Processes, 9784431546344, 137, 147, Springer Japan, 01 Nov. 2014, [Peer-reviewed]
    English, In book
  • Single-Cell Imaging of Caspase-1 Dynamics Reveals an All-or-None Inflammasome Signaling Response
    Ting Liu; Yoshifumi Yamaguchi; Yoshitaka Shirasaki; Koichi Shikada; Mai Yamagishi; Katsuaki Hoshino; Tsuneyasu Kaisho; Kiwamu Takemoto; Toshihiko Suzuki; Erina Kuranaga; Osamu Ohara; Masayuki Miura
    CELL REPORTS, 8, 4, 974, 982, Aug. 2014, [Peer-reviewed]
    English, Scientific journal
  • In Vivo Monitoring of Caspase Activation Using a Fluorescence Resonance Energy Transfer-Based Fluorescent Probe
    Yoshifumi Yamaguchi; Erina Kuranaga; Yu-ichiro Nakajima; Akiko Koto; Kiwamu Takemoto; Masayuki Miura
    REGULATED CELL DEATH PT A: APOPTOTIC MECHANISMS, 544, 299, 325, 2014, [Peer-reviewed]
    English, In book
  • Local apoptosis modulates early mammalian brain development through the elimination of morphogen-producing cells.
    Keiko Nonomura; Yoshifumi Yamaguchi; Misato Hamachi; Masato Koike; Yasuo Uchiyama; Kenichi Nakazato; Atsushi Mochizuki; Asako Sakaue-Sawano; Atsushi Miyawaki; Hiroki Yoshida; Keisuke Kuida; Masayuki Miura
    Developmental cell, 27, 6, 621, 34, 23 Dec. 2013, [Peer-reviewed], [International Magazine]
    English, Scientific journal
  • How to form and close the brain: Insight into the mechanism of cranial neural tube closure in mammals
    Yoshifumi Yamaguchi; Masayuki Miura
    Cellular and Molecular Life Sciences, 70, 17, 3171, 3186, Sep. 2013, [Peer-reviewed]
    English
  • Live imaging of apoptosis in a novel transgenic mouse highlights its role in neural tube closure
    Yoshifumi Yamaguchi; Naomi Shinotsuka; Keiko Nonomura; Kiwamu Takemoto; Keisuke Kuida; Hiroki Yosida; Masayuki Miura
    JOURNAL OF CELL BIOLOGY, 195, 6, 1047, 1060, Dec. 2011, [Peer-reviewed]
    English, Scientific journal
  • Simultaneous expression of different transgenes in neurons and glia by combining in utero electroporation with the Tol2 transposon-mediated gene transfer system
    Ayako Yoshida; Yoshifumi Yamaguchi; Keiko Nonomura; Koichi Kawakami; Yoshiko Takahashi; Masayuki Miura
    GENES TO CELLS, 15, 5, 501, 512, May 2010, [Peer-reviewed]
    English, Scientific journal
  • Grainyhead-related transcription factor is required for duct maturation in the salivary gland and the kidney of the mouse
    Yoshifumi Yamaguchi; Shigenobu Yonemura; Shinji Takada
    DEVELOPMENT, 133, 23, 4737, 4748, Dec. 2006, [Peer-reviewed]
    English, Scientific journal
  • Gene trap screening as an effective approach for identification of Wnt-responsive genes in the mouse embryo
    Y Yamaguchi; S Ogura; M Ishida; M Karasawa; S Takada
    DEVELOPMENTAL DYNAMICS, 233, 2, 484, 495, Jun. 2005, [Peer-reviewed]
    English, Scientific journal
■ Other Activities and Achievements
■ Books and other publications
■ Lectures, oral presentations, etc.
  • A plastic remodeling of white adipose tissues and skeletal muscles in a hibernator under the cold
    Yoshifumi Yamaguchi
    第23回アディポサイエンス研究会, 18 Aug. 2018, Japanese, Invited oral presentation
    [Invited], [Domestic Conference]
  • 冬眠する哺乳類シリアンハムスターを用いた冬眠能の解析
    山口良文
    モロシヌス研究会2018, 22 Jun. 2018, Japanese, Oral presentation
    [Domestic Conference]
  • Elucidating the roles and regulation of cell death in mammalian development and physiology
    Yoshifumi Yamaguchi
    Australia-Japan Meeting on Cell Death, 23 May 2018, English, Nominated symposium
    [International presentation]
  • 冬眠する哺乳類シリアンハムスターの全身性代謝変化
    山口良文
    生理研研究会「生命のエネルギー獲得戦略における多様性と共通原理の理解にむけて」, 27 Apr. 2018, Japanese, Invited oral presentation
    [Invited], [Domestic Conference]
  • Understanding seasonal body remodeling in mammalian hibernation
    Yoshifumi Yamaguchi
    KEY-Forum "Stem Cell Traits and Developmental Systems" (Kumamoto, Japan), 12 Jan. 2018, English, Invited oral presentation
    [Invited], [International presentation]
  • 哺乳類の冬眠を可能とする全身性代謝変化の分子基盤
    山口良文
    ConBio2017（日本分子生物学会年会、神戸）, 09 Dec. 2017, Japanese, Invited oral presentation
    [Invited], [International presentation]
  • カスパーゼ１活性の可視化から明らかになったインフラマソーム活性化様式
    山口良文; 劉霞; 三浦正幸
    日本病態プロテアーゼ学会, 12 Aug. 2017, Japanese, Invited oral presentation
    [Invited], [Domestic Conference]
  • 冬眠可能な生体状態とは？シリアンハムスターを用いたアプローチ
    山口良文
    第一回冬眠休眠研究会, 22 Jul. 2017, Japanese, Oral presentation
    [Domestic Conference]
  • Apoptosis is required for maintaining the character of the midbrain roof plate after the neural tube closure.
    Yamaguchi, Y; Matsumoto, Y; Hamachi, M; Yoshida; Miura, M
    第40回日本神経科学大会, 20 Jul. 2017, English, Poster presentation
    [International presentation]
  • 哺乳類の代謝が全身性に変わる二つの局面〜「胚発生」と「冬眠」
    山口良文
    がんと代謝研究会, 14 Jul. 2017, Japanese, Public discourse
    [Invited], [Domestic Conference]
  • 冬眠する哺乳類シリアンハムスターに学ぶ、冬眠可能な生体状態とは？
    山口良文
    岡山実験動物研究会, 07 Jul. 2017, Japanese, Invited oral presentation
    [Invited], [Domestic Conference]
  • Rewiring of Embryonic Energy Metabolism During Mouse Chorioallantoic Branching
    Yoshifumi Yamaguchi
    50th Annual Meeting of the Japanese Society of Developmental Biologists, 10 May 2017, English, Invited oral presentation
    [Invited], [International presentation]
  • Investigation of mechanisms for skeletal muscle maintenance during hibernation season in a mammalian hibernator, Syrian golden hamster.
    Yamaguchi, Y; Fujimoto, T; Ando, L; Chayama, Y; Anegawa, D; Taii, H; Tamura, Y; Shigenobu, S; Masayuki Miura, M
    94th Annual Meeting of Physiological Society of Japan., (Hamamatsu), 28 Mar. 2017, English, Poster presentation
    [International presentation]
  • 冬眠に先駆けて誘導される白色脂肪組織リモデリングの規定とその分子メカニズ ムの探索
    茶山由一; 安藤理沙; 重信秀治; 佐藤祐哉; 姉川大輔; 藤本貴之; 泰井宙輝; 田村豊; 三浦正幸; 山口良文
    第１２回環境生理プレコングレス, 27 Mar. 2017, Japanese, Oral presentation
    [Domestic Conference]
  • シリアンハムスターが冬眠期に示す骨格筋変化の解明
    山口良文; 藤本貴之; 茶山由一; 安藤理沙; 姉川大輔; 泰井宙輝; 田村豊; 重信秀治; 三浦正幸
    第１２回環境生理プレコングレス, 27 Mar. 2017, Japanese, Oral presentation
    [Domestic Conference]
  • 哺乳類胚発生と冬眠における代謝変化
    山口良文; 宮沢英延; 茶山由一; 藤本貴之; 三浦正幸
    第４回 発生における代謝を考える会（京都）, 20 Feb. 2017, Japanese, Oral presentation
    [Domestic Conference]
  • 哺乳類の冬眠〜季節環境に応じた全身性の代謝抑制と体温制御
    山口良文
    第1回Biothermology Workshop - 生命システムの熱科学 -, 10 Dec. 2016, Japanese, Invited oral presentation
    [Invited], [Domestic Conference]
  • 哺乳類の冬眠とは？～冬を乗り切るための代謝変化のメカニズム
    山口良文
    東京大学発達保育実践政策学センター 第４回発達基礎科学セミナー, 21 Nov. 2016, Japanese, Public discourse
    [Invited], [Domestic Conference]
  • 死細胞からのシグナル放出のイメージング
    山口良文
    千里ライフサイエンスセミナーK4 免疫・感染症シリーズ第６回「ワクチン、アジュバント開発研究の最前線」, 15 Nov. 2016, Japanese, Invited oral presentation
    [Invited], [Domestic Conference]
  • 冬眠する哺乳類シリアンハムスターに学ぶ、冬眠可能な生体状態とは？
    山口良文
    第１回オモロイ生き物研究会, 22 Oct. 2016, Japanese, Oral presentation
    [Domestic Conference]
  • 冬眠する哺乳類シリアンハムスターに学ぶ、冬眠可能な生体状態とは？
    山口良文
    広島大学大学院理学研究科第二回細胞生物学研究室セミナー, 02 Sep. 2016, Japanese, Public discourse
    [Domestic Conference]
  • Investigation of mechanisms for the resistance to ischemia-reperfusion stress during hibernation period in Syrian hamsters
    Anegawa, D; Chayama, Y; Ando, L; Shigenobu, S; Miura; M. Yamaguchi, Y
    15th International Hibernation Symposium (Las Vegas, USA), 01 Aug. 2016, English, Oral presentation
    [International presentation]
  • Molecular remodeling of inguinal adipose tissue precedes hibernation period in Syrian golden hamster
    Chayama, Y; Ando, L; Shigenobu, S; Tamura, Y; Miura, M; Yamaguchi, Y
    15th International Hibernation Symposium (Las Vegas, USA), 01 Aug. 2016, English, Poster presentation
    [International presentation]
  • Evidence for systemic remodeling prior to hibernation in the Syrian hamster (Mesocricetus auratus),
    Yamaguchi, Y; Chayama, Y; Ando, L; Anegawa, D; Shigenobu, S; Fujimoto, T; Taii, H; Tamura, Y; Miura, M
    15th International Hibernation Symposium (Las Vegas, USA), 01 Aug. 2016, English, Oral presentation
    [International presentation]
  • Pre-hibernation remodeling accompanies decreases in body temperature and body weight in a facultative mammalian hibernator, Syrian hamster
    Yamaguchi, Y; Chayama, Y; Ando, L; Tamura, Y; Miura, M
    日本神経科学大会, 20 Jul. 2016, English, Poster presentation
    [International presentation]
  • Elimination of the boundary cells by apoptosis in the dorsal midline of the midbrain after the neural tube closure
    Yamaguchi, Y; Matsumoto, M; Hamachi, M; Nonomura, K; Shinotsuka, N; Miura, M
    Gordon Research Conference “Cell Death” (Girona, Spain), 03 Jul. 2016, English, Poster presentation
    [International presentation]
  • 死細胞のライブイメージング観察から視えるもの
    山口良文
    第８１回日本インターフェロン学会, 23 Jun. 2016, Japanese, Invited oral presentation
    [Invited], [Domestic Conference]
  • Evidence for systemic remodeling prior to hibernation in the Syrian hamster (Mesocricetus auratus),
    Yamaguchi, Y; Chayama, Y; Ando, L; Shigenobu, S; Anegawa, D; Fujimoto, T; Tamura, Y; Miura, M
    NIBB conference: Evolution of Seasonal Timers (Okazaki, Japan), 23 Apr. 2016, English, Oral presentation
    [International presentation]
  • Metabolic reorganization that supports growth of mouse embryos during the mid-gestation stage
    Miyazawa, H; Yamaguchi, Y; Sugiura, Y; Yamamoto, M; Honda, K; Kondo, K; Yamamoto, T; Suematsu, M; Miura, M
    CDB Symposium 2016, Size in Development: Growth, Shape and Allometry., 28 Mar. 2016, English, Poster presentation
    [International presentation]
  • 冬眠する哺乳類シリアンハムスターに学ぶ冬眠するための準備とは？
    山口良文
    北海道大学遺伝子病制御研究所動物機能医科学研究室セミナー, 23 Mar. 2016, Japanese, Public discourse
    [Invited], [Domestic Conference]
  • 冬眠期の腎臓における虚血再灌流ストレス耐性機構の解明に向けて
    姉川大輔; 茶山由一; 安藤理紗; 重信秀治; 三浦正幸; 山口良文
    第９３回日本生理学会大会, 22 Mar. 2016, English, Poster presentation
    [International presentation]
  • Evidence for systemic pre-hibernation remodeling in a mammalian hibernator, Syrian golden hamster
    Yamaguchi, Y; Ando, L; Chayama, Y; Anegawa, D; Fujimoto, T; Shigenobu, S; Tamura, Y; Miura
    第９３回日本生理学会大会, 22 Mar. 2016, English, Poster presentation
    [International presentation]
  • 冬眠する哺乳類シリアンハムスターが前冬眠期に示す生体状態変化〜基礎体温と体重のセットポイント変化について
    山口良文; 茶山由一; 安藤理沙; 姉川大輔; 重信秀治; 田村豊; 三浦正幸
    第11回環境生理プレコングレス（札幌）, 21 Mar. 2016, Japanese, Oral presentation
    [Domestic Conference]
  • 虚血再灌流ストレスによる組織障害に対しての冬眠期における耐性機構の解明
    姉川大輔; 茶山由一; 安藤理紗; 三浦正幸; 山口良文
    新学術領域研究 酸素生物学＆ダイイングコード 合同若手会議, 26 Jan. 2016, Japanese, Poster presentation
    [Domestic Conference]
  • 哺乳類胎盤接続期に生じる胚のエネルギー代謝状態再編成の解明
    宮沢英延; 山口良文; 杉浦悠毅; 山本正道; 本多久楽々; 山本鉱広; 末松誠; 三浦正幸
    新学術領域研究 酸素生物学＆ダイイングコード合同若手会議, 26 Jan. 2016, Japanese, Poster presentation
    [Domestic Conference]
  • What enables hibernation in mammals? ~ Identification of body remodeling for hibernation in the pre-hibernation period
    Yoshifumi Yamaguchi
    第３８回日本分子生物学会、ワークショップ「異種間比較が解き明かす生命システムの普遍性と多様性」, 01 Dec. 2015, Japanese, Invited oral presentation
    [Invited], [International presentation]
  • 冬眠する哺乳類に学ぶ代謝変化
    山口良文
    脳心血管抗加齢研究会2015, 28 Nov. 2015, Japanese, Invited oral presentation
    [Invited], [Domestic Conference]
  • Imaging Cell Death.
    Yoshifumi Yamaguchi
    Japan Australia Meeting on Cell Death (WEHI, Melbourne, Australia), 21 Oct. 2015, English, Oral presentation
    [International presentation]
  • アポトーシスとパイロトーシスのライブイメージング観察
    山口良文
    第2４回日本Cell Death学会学術集会, 12 Jul. 2015, Japanese, Invited oral presentation
    [Invited], [Domestic Conference]
  • 細胞死のライブイメージング
    山口良文
    第１５回蛋白質科学会年会ワークショップ「細胞死を起点とする生体制御ネットワーク」(徳島）, 24 Jun. 2015, Japanese, Invited oral presentation
    [Invited], [Domestic Conference]
  • 冬眠を可能とする分子機構同定に向けた網羅的遺伝子発現解析
    山口良文; 茶山由一; 安藤理沙; 重信秀治; 田村豊; 三浦正幸
    第９２回日本生理学会大会, 22 Mar. 2015, Japanese, Poster presentation
    [Domestic Conference]
  • 異なる細胞死動態の単一細胞ライブイメージング
    山口良文
    第87回日本生化学会 細胞死の多様性と生体応答〜細胞死の生物学の新たな側面〜、, 18 Oct. 2014, Japanese, Oral presentation
    [Domestic Conference]
  • 哺乳類の代謝が全身性に変わるとき〜胚発生と冬眠
    山口良文
    第７回シンフォニー（東京）, 14 Sep. 2014, Japanese, Invited oral presentation
    [Invited], [Domestic Conference]
  • Modulation of early mammalian brain development through local apoptotic elimination of morphogen-producing cells. Cellular Dynamics in Early Mammalian Embyrogenesis
    Yoshifumi Yamaguchi
    Japanese Society of Developmental Biology (Nagoya), 28 May 2014, English, Invited oral presentation
    [Invited], [International presentation]
■ Syllabus
  • 環境分子生物学特論Ⅰ, 2024年, 修士課程, 環境科学院
  • 分子生物学基礎論, 2024年, 修士課程, 環境科学院
  • 分子生物学基礎論, 2024年, 修士課程, 環境科学院
  • 生物圏科学実習Ⅰ, 2024年, 修士課程, 環境科学院
  • 生物圏科学実習Ⅱ, 2024年, 修士課程, 環境科学院
  • 環境と人間, 2024年, 学士課程, 全学教育
  • 一般教育演習(ﾌﾚｯｼｭﾏﾝｾﾐﾅｰ), 2024年, 学士課程, 全学教育
■ Affiliated academic society
  • 日本筋学会
  • THE MOLECULAR BIOLOGY SOCIETY OF JAPAN
  • 日本 Cell Death学会
  • THE JAPANESE BIOCHEMICAL SOCIETY
  • THE PHYSIOLOGICAL SOCIETY OF JAPAN
  • 日本神経科学学会
  • 日本発生生物学会
  • 日本時間生物学会
■ Research Themes
  • 冬眠達成機構の分子的探求
    科学研究費助成事業
    01 Apr. 2023 - 31 Mar. 2028
    山口 良文; 渡邊 正知
    本研究課題の先行研究（学術変革領域研究(B)）において得た冬眠発動そのものに異常を示すハムスターDEG1 (Differentially Expressed Gene 1)遺伝子変異体について、その体温変動パターンについて詳細な解析を行った。その結果、冬眠発動までのタイミングだけでなく、深冬眠や中途覚醒の継続時間、冬眠期間の長さなど、冬眠表現型の多くにおいて、正常個体とは明らかに異なる変化を認めた（論文投稿準備中）。
    この解析の過程で、比較対照となる野生型個体の冬眠時の体温変化も詳細に解析し、冬眠明けには体温日周リズムの夏型回帰（長日化）が外界環境に関わらず生じることを見出し報告した（Nakagawa & Yamaguchi, Proc B, 2023）。こうした年単位にわたる膨大な時系列体温データを簡便に解析するため、体温変動解析プログラムの開発も進めた。またDEG1の遺伝子産物であるタンパク質の冬眠時の挙動についても解析を進め、体温変化に伴う変化を見出した。さらに冬眠の際の体温変化によって生じるmRNA末端の構造変化についても見出したので報告した（Sone et al, BBRC, 2023）。
    一方、冬条件と夏条件との間で大幅に発現変動するSDGs (Seasonal Difference Genes)についても、その機能変異体の作出準備を進めた。
    さらにこれら新たに作出する遺伝子変異体を用いて安定した冬眠誘導実験を行うため、冬仕様の条件での飼育が可能な冬眠誘導専用の低温飼育室を増設するとともに、その対照となる夏仕様条件での飼育が可能な恒温恒湿飼育室も新設した。これらにより、研究が加速する態勢が整った。
    日本学術振興会, 学術変革領域研究(A), 北海道大学, 23H04940
  • Hibernation biology 2.0: understanding regulated hypometabolism and its function
    Grants-in-Aid for Scientific Research
    01 Apr. 2023 - 31 Mar. 2028
    山口 良文
    Japan Society for the Promotion of Science, Grant-in-Aid for Transformative Research Areas (A), 23A303
  • 冬眠生物学2.0 総括班
    科学研究費助成事業 学術変革領域研究(A)
    01 Apr. 2023 - 31 Mar. 2028
    山口 良文
    日本学術振興会, 学術変革領域研究(A), 北海道大学, 23H04939
  • 冬季に生じる哺乳類の脂質代謝生理変化を担う体液性因子の解析
    科学研究費助成事業
    01 Apr. 2023 - 31 Mar. 2026
    山口 良文
    冬眠する哺乳類は、寒冷・飢餓などの厳しい環境下での長期生存のため、熱産生と代謝を積極的に抑制した「冬眠」を行う。特に小型の冬眠哺乳類は10度以下の低体温・不動状態となるが、ヒトやマウスなど多くの非冬眠哺乳類は長時間の低体温下では臓器恒常性を維持できず死に至ることを考えると、この冬眠できる能力は驚異的である。冬眠能は、低温耐性・健康肥満・動脈硬化耐性・廃用性筋萎縮耐性・季節性の体の変換など、その機構が解明されれば医学・創薬応用の可能性も高い種々の性質から構成されるが、未だその分子機構は殆ど不明である。我々はこれまでに、冬眠哺乳類シリアンハムスター(Mesocricetus auratus,)が長期間の寒冷短日刺激によって冬仕様の体に変化する際に誘導される全身代謝変化・組織変化を明らかにするとともに、シリアンハムスターが常時備える低温耐性には高ビタミンE保持能が重要であることを明らかにしてきた。本研究では、冬眠の際の全身代謝生理変化を誘導する全身性シグナルの同定を目指し、ビタミンEとコレステロールの代謝変化に着目する。これら二つの脂質関連分子の生体内動態を季節および冬眠という観点から詳細に明らかにするとともに、その変化の生理的意義を検証する。さらに季節や冬眠に即してこれらの分子量を変化させる全身性シグナルとして、体液性因子に着目しその活性測定と同定を行う。以上の解析から、冬季に生じる脂質代謝系変化の制御機構に迫る。
    日本学術振興会, 基盤研究(B), 北海道大学, 23K28012
  • Muscle Atrophy Resistance in Hibernating Animals
    Grants-in-Aid for Scientific Research
    01 Apr. 2022 - 31 Mar. 2026
    宮崎 充功; 坪田 敏男; 山口 良文; 渡邊 正知; 下鶴 倫人
    冬眠動物には、5-6ヵ月におよぶ冬眠前後で筋肉量や筋力がほとんど衰えない、骨格筋萎縮耐性ともいえる未解明の生理機能が存在する。本研究では冬眠を「長期間の身体不活動状態の継続」と捉え、冬眠動物がいかなる適応機構を用いて骨格筋萎縮耐性を獲得するのかを解明し、さらに非冬眠動物のマウスで “衰えない筋肉” を再現させるのが本研究の目的である。この目標を達成するために、本研究では特に課題1) 冬眠動物の骨格筋に共通して発現誘導・抑制される遺伝子群(DEGs)の網羅的解析を基盤とし、課題2) 骨格筋衛星細胞を用いて冬眠誘導性遺伝子の発現制御による筋タンパク質代謝調節機構を明らかにする。さらに課題3) 冬眠誘導性遺伝子のマウス骨格筋でのin vivo機能解析を通じ、冬眠動物の骨格筋萎縮耐性能を非冬眠動物であるマウス骨格筋で再現させる。
    研究開始2年目である2023年度においては、2022年度に完了させた冬眠動物の骨格筋における冬眠誘導性遺伝子の探索結果を基盤とし、絞り込みを行った候補遺伝子の全身性ノックアウトマウスおよび骨格筋組織特異的ノックアウトマウスの作出に着手した。ファウンダーマウスはすでに作出を完了しており、現在その機能解析を進行中である。また冬眠動物骨格筋からの組織幹細胞単離方法の確立および低温誘導性細胞死に対する抵抗性の分子機構解明についても検討を進めており、その結果の一部については国際学会および招待講演にて報告をしている。
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Hiroshima University, 23K24697
  • Novel Strategy to Prevent Skeletal Muscle Atrophy Based on "Muscle Atrophy Resistance" in Hibernating Animals
    Grants-in-Aid for Scientific Research
    01 Apr. 2022 - 31 Mar. 2026
    宮崎 充功; 坪田 敏男; 山口 良文; 渡邊 正知; 下鶴 倫人
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Hiroshima University, 22H03439
  • Epigenetic mechanisms underlying seasonal body remodeling of a mammalian hibernator
    Grants-in-Aid for Scientific Research
    30 Jun. 2022 - 31 Mar. 2024
    Sone Masamitsu
    When exposed to cold and short-photoperiod environment, after a few-month latent period, Syrian hamsters start hibernation, in which they extremely reduce their metabolism. In hibernation, they repeat the cycles of deep torpor, in which their body temperature become below 10 degree C, and periodic arousal, in which they recover euthermic state or 37 degree C body temperature. After hibernation of a few month, they spontaneously cease hibernation and undergo post-hibernation. To address the mechanisms underlying such status shifts, I focused on chemical modification of chromatin called epigenetic modification, and established methods to analyze it globally.
    Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Research (Exploratory), Hokkaido University, 22K19320
  • Mammalian hibernation biology ~ survival strategies via hypometabolism and hypothermia
    Grants-in-Aid for Scientific Research Grant-in-Aid for Transformative Research Areas (B)
    02 Oct. 2020 - 31 Mar. 2023
    山口 良文
    Japan Society for the Promotion of Science, Grant-in-Aid for Transformative Research Areas (B), 20B303
  • 哺乳類の低代謝・低体温による生存戦略の統合的理解
    科学研究費助成事業 学術変革領域研究(B)
    02 Oct. 2020 - 31 Mar. 2023
    山口 良文
    本研究領域「冬眠生物学」では、最先端の計測技術および遺伝子工学技術を駆使した分野横断型チームにより、哺乳類生理学に残された大きな課題である「冬眠・休眠実行を担う分子ネットワークの解明」を目的とする。R3年度も昨年度に引き続き、総括班として主に以下の活動を行った。
    1. オンライン領域会議: 年２回オンライン開催し、各計画研究の企画調整、推進方針の決定を行い、領域内研究者間での情報交換、研究資材の相互利用など有機的な連携体制の強化を昨年度に引き続き進めた
    2. 冬眠休眠研究会の開催：総括班代表者の山口が中心となり、日本の冬眠休眠研究者が集う冬眠休眠研究会第４回を開催した。当初ハイブリッド開催予定だったがCovid-19感染状況が悪化したため、完全オンライン開催となった。参加者の交流を促進するためオンライン交流システムを導入した。本領域研究者だけでなく、幅広い分野から参加者80名以上が集まる盛況となった。
    3. 学会シンポジウム共催:本年度は日本分子生物学会年会および日本生理学会において哺乳類の冬眠・休眠を話題としたセッションを開催した。まだ研究者数の少ない冬眠休眠研究分野であるが、多数の参加者を得ることができ、本分野への関心の高さがうかがえた。
    4. 冬眠研究用機器の開発:哺乳類の冬眠休眠研究に活用できる、体温・活動量の長期計測を可能とするデバイスの試作機の検証を個体レベルで行うとともに、さらなる改良を試み二号機の試作を行った。
    日本学術振興会, 学術変革領域研究(B), 北海道大学, 20H05765
  • 冬眠発動の分子機構：深冬眠実行の分子基盤と飢餓性休眠との共通性の解明
    科学研究費助成事業 学術変革領域研究(B)
    02 Oct. 2020 - 31 Mar. 2023
    山口 良文; 渡邊 正知
    2年目となる本年度は、昨年度に引き続きDEG1欠損シリアンハムスターおよびマウスの、冬眠および飢餓誘導性休眠への関与を個体レベルで検証した。昨年度に確認した、DEG1はマウスにおいて飢餓誘導性の休眠発動に必要であるという結果が追認された。一方、DEG1欠損シリアンハムスターにおいても十分数の個体において冬眠誘導実験を行った。その結果、野生型個体の多くが数ヶ月で冬眠を発動する短日・寒冷環境での長期飼育下でも、DEG1欠損シリアンハムスターの約半数は冬眠を発動しなかった。のこり半数の個体は冬眠したが、短日・寒冷環境下に置かれてから冬眠を発動するまでの日数が延長、すなわち冬眠の発動が遅延した。これらの実験と並行して、DEG1遺伝子の冬眠時の発現変動をmRNAおよびたんぱく質の両レベルで確認することに成功した。
    さらなる展開として、DEG1欠損により冬眠・休眠発動が阻害される分子メカニズムを同定するべく、DEG1遺伝子破壊個体と野生型個体との間で発現変動する遺伝子の同定をRNA-seqを用いて試みた。また、生体脂質組成変化を通じて冬眠・休眠に影響を与える可能性も検討するため、リピドミクス分析の条件検討を開始した。これらオミクス解析結果の詳細な解析は最終年度に行い、DEG1が冬眠発動に影響を与える機序に迫る。これらの解析と並行して、DEG1欠損シリアンハムスターの行動解析実験も進めた。冬眠研究用に新規開発した、活動量・体温の長期計測が可能なデータロガーを用いて、野生型と異なる活動の検出に成功した。
    日本学術振興会, 学術変革領域研究(B), 北海道大学, 20H05766
  • Investigation of skeletal muscle remodeling for hibernation in a mammalian hibernator Syrian hamster
    Grants-in-Aid for Scientific Research
    01 Apr. 2019 - 31 Mar. 2022
    YAMAGUCHI YOSHIFUMI
    In this study, we clarified the skeletal muscle changes that occur in the process of remodeling the whole body into a body suitable for hibernation in a mammalian hibernator Syrian hamster. Specifically, we identified that Syrian hamsters reduce skeletal muscle mass during the pre-hibernation period, but maintain skeletal muscle mass during hibernation period. We then described the distribution of muscle fiber types in the back muscle that acts on shivering thermogenesis, and its changes during the body remodeling. We also set-up functional analysis of candidate genes that were identified as those assumed to be involved in the remodeling of skeletal muscles. These findings provide the basis for approaching mechanisms of the muscular atrophy tolerance in mammalian hibernators.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Hokkaido University, 19H04046
  • Investigation of mechanisms inducing spontaneous hypothermia in a mammalian hibernator
    Grants-in-Aid for Scientific Research
    29 Jun. 2018 - 31 Mar. 2021
    Yamaguchi Yoshifumi
    Hibernation is the adaptive strategy that enables long-term survival in extreme environments such as cold, dryness, and starvation by suppressing metabolism systemically. During the hibernation period, the Syrian hamster, a small mammal that hibernates, repeats torpor-arousal cycles, during with a body temperature dramatically changes from 10 or less to 37 degrees celsius. However, mechanisms controlling the torpor-arousal cycle is still largely unknown. To approach this question, we identified DTIG (Deep-torpor-induced genes), a group of genes whose expression levels in tissues differ greatly between torpor and arousal. Furthermore, we succeeded in producing genetically modified animals for one of these genes.
    Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Research (Exploratory), Hokkaido University, 18K19321
  • Investigation of mechanisms enabling mammalian hibernation
    Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
    01 Apr. 2016 - 31 Mar. 2019
    Yamaguchi Yoshifumi
    Hibernation is a strategy that enables long-term survival at hypothermia by systemic metabolic suppression under extreme environments such as cold, dryness, and starvation. Mechanisms for this remarkable "hibernation tolerance" granted to hibernating animal is, however, poorly understood yet, whereas it is suggested that the hibernation tolerance is partly induced from the pre-hibernation period to the hibernation period. In this study, we attempted to elucidate the mechanism of hibernation tolerance in a model hibernating animal, Syrian hamsters. By profiling basal body temperature and global gene expression at different timepoints, we found that changes in basal body temperature and white adipose tissue remodeling take place prior to hibernation in Syrian hamsters.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), 16H05127
  • Live cell imaging of regulated necrosis
    Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    01 Apr. 2016 - 31 Mar. 2019
    MURAI Shin; YAMAGUCHI Yoshifumi
    Regulated necrosis is a regulated form of necrosis that depends on RIPK3 and MLKL. To monitor the induction of regulated necrosis, we have designed FRET biosensor (KLN) which inserted the linker sequence derived from MLKL between CFP and YFP. Since KLN expression suppressed the cell proliferation, the KLN linker sequence was modified. As the result, FRET biosensor without cytotoxicity was developed and termed as SMART. SMART can monitor regulated necrosis, but not apoptosis or necrosis in vitro, indicating that SMART is a specific sensor to regulated necrosis. FRET was not observed by the knockdown of RIPK3 expression or the inhibition of RIPK3 activity, suggesting that SMART can monitor RIPK3 activity which is required the induction of regulated necrosis. Since the unphosphorylated SMART mutant can also monitor RIPK3 activation by its FRET, it was concluded that FRET of SMART is required for the interaction of RIPK3 but not phosphorylation by RIPK3.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Toho University, 16K01378
  • Establishment of international research community on cell death
    Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
    06 Nov. 2015 - 31 Mar. 2019
    Tanaka Masato
    This project aimed to establish the international research community on cell death. For this purpose, we performed following activities. 1. we held a closed meeting with Australian cell death researchers in Tokyo. We also held a closed international meeting for young investigators simultaneously. 2. We supported international personnel exchange to promote collaborative research. 3. We supported international collaborative research and published 8 papers in international scientific journals.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area), Tokyo University of Pharmacy and Life Science, 15K21753
  • Homeostatic regulation by various type of cell death
    Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
    10 Jul. 2014 - 31 Mar. 2019
    Tanaka Masato; OIKAWA Akira
    This research project aimed to analyze the molecular mechanisms of several types of cell death and biological responses initiated by them to elucidate physiological and pathological roles played by each type of cell death. For this purpose the steering committee performed following activities. 1 We held annual meetings with all members of "dying code" research group to exchange research findings within this group. 2. We performed several research-supporting activities to promote not only their own researches, but also collaborative researches among members of this group. 3. We held domestic and international symposiums on cell death. 4. We held joint collaborative meeting for young investigators. 5. We established the website and published newsletters. 6. We performed several outreach activities.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area), Tokyo University of Pharmacy and Life Science, 26110001
  • Visualization and significance of various types of regulated cell death in vivo
    Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
    10 Jul. 2014 - 31 Mar. 2019
    Yamaguchi Yoshifumi
    To elucidate dynamics and significance of various types of regulated cell death in vivo, we developed novel fluorescent probes that allow us to detect pyroptosis and necroptosis in a real-time manner (Cell Rep 2014, Nature Commun 2018). To address the roles and regulation of cell death during mouse development, we analyzed mice deficient for genes regulating apoptosis and revealed involvement of apoptotic machinery in cellular movement during and after neural tube closure, during which a lot of cell death occur with dramatic rewiring of energy metabolic pathway (Dev Cell 2015, Development 2017, Genes Cells 2018, BMC Dev Biol 2018). In addition, we also found that alternative autophagic cell death compensates for apoptosis-deficiency during development (Cell Death Differ 2017).
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area), 26110005
  • An attempt to generate transgenic hamsters for hibernation research
    Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research
    01 Apr. 2016 - 31 Mar. 2018
    Yamaguchi Yoshifumi
    To elucidate the mysteries of hibernation of mammals whose molecular mechanism is still unknown, we aimed to produce transgenic Syrian hamsters useful for hibernation research by applying recently developed genome editing technology to a mammalian hibernator, Syrian hamsters. Because it is known that oocyte of Syrian hamsters is vulnerable to light, we attempted to apply the GONAD method, a recently developed method which introduces Cas9 complexes into oviducts by electroporation. We succeeded in introducing the nucleic acid itself into the fertilized egg, but failed to obtain genetically modified animals. The reasons for this is unclear. GONAD conditions for mouse or our breeding environments in the same room with mice might not be suitable for Syrian hamsters. We will improve these points in future.
    Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Exploratory Research, The University of Tokyo, 16K15114
  • 冬眠を可能とする生体状態の可視化とその誘導メカニズムの解明
    2012 - 2015
    山口 良文
    冬眠は、寒冷かつ餌の枯渇といった極限環境を、代謝活動を劇的に減少させ低体温状態で乗り切る驚異的な現象です。しかし、冬眠できる哺乳類と、私たちヒトを含む多くの冬眠出来ない哺乳類との差は何なのか、殆どわかっていません。本研究では、冬眠制御に重要な脳中枢と末梢臓器との相互作用という観点から、冬眠可能な生体状態の実体を最新の解析技術を用いて明らかにし、その制御機構に迫ることを目指します。その知見は、虚血再灌流障害予防、神経変性疾患、糖尿病予防などさまざまな医学的応用が期待されます。
    科学技術振興機構, 戦略的な研究開発の推進/戦略的創造研究推進事業/さきがけ, 12101055
  • マウス初期胚発生過程で細胞死が周辺細胞動態に与える影響の解明
    科学研究費助成事業 新学術領域研究(研究領域提案型)
    01 Apr. 2012 - 31 Mar. 2014
    山口 良文
    本研究課題は、ほ乳類初期胚で生じる劇的な形態形成運動すなわち神経管閉鎖過程において、細胞死(アポトーシス)が周辺組織の組織動態にいかなる影響を与えるのか解明することを目的としている。具体的には、アポトーシスが多数見られかつその必要性が知られている、ほ乳類の頭部神経管閉鎖過程に着目し解析を行なった。
    まず、アポトーシスが顕著に認められる、前脳前端のanterior neural ridge(ANR)と呼ばれる領域に着目した。アポトーシス欠損変異体のライブイメージング解析から、アポトーシス欠損により、この領域の運動性が損なわれ、組織融合がうまくいかないことが判明した 。アポトーシス欠損変異体では、本来これらの領域からアポトーシスにより除去されるFGF8発現細胞がANRに蓄積し、その結果FGF8蛋白質が前脳全域へと拡散分布してしまうこと、 さらにその結果、前脳領域の細胞分化パターンが異常になることが明らかとなった。このように、モルフォゲン産生細胞がアポトーシスにより発生の適切な時期までに除去されることが、脳の正常な形態形成およびパターニング必要であることが、本研究課題により初めて解明された（Nonomura et al., Dev Cell, 2013）。
    一方、中脳－後脳領域でのアポトーシスについては、高解像度ライブイメージング系を構築し、神経管閉鎖運動および引き続いて生じる組織リモデリング過程の解析を行なった。その結果、アポトーシス欠損により神経管閉鎖後の上皮組織形態形成運動が障害されている様子が明らかとなった。その意義と機構の解明は今後の新しい研究課題といえる。
    日本学術振興会, 新学術領域研究(研究領域提案型), 東京大学, 24116704
  • Approach to reveal dynamics of caspase activation in maintainingbrain homeostasis
    Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research
    2011 - 2012
    YAMAGUCHI Yoshifumi
    Caspases are evolutionary conserved cystein protease. In this study, we tried to reveal dynamics of caspase activation in maintaining brain homeostasis. For this purpose, we utilized two novel probes that allow us to detect caspases-1 or caspase-3 in real-time. However, we have not detected weak or mild activation of those caspases in the brain derived from sleep-deprived mouse or in primary cell culture. These results suggest that further improvement in detection method will be needed to observe weak or mild activation of caspases by these probes.
    Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Exploratory Research, The University of Tokyo, 23659032
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