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Shigemoto Kazuhiro

    Senior Fellow　Vice-president
Last Updated :2025/04/14

Researcher Information

J-Global ID

Research Interests

  • Sarcopenia, Frailty, muscle atrophy, neuromuscular disease, neuromuscular junction, metabolic shift   

Association Memberships

  • Society for Neuroscience   The ROYAL SOCIETY of MEDICINE   American Academy of Neurology   日本分子生物学会   日本神経免疫学会   日本神経科学会   日本老年医学会   Japanese Society of Neurology   Japanese Association on Sarcopenia and Frailty   Japan Society for Biomedical Gerontology   

Published Papers

MISC

Research Grants & Projects

  • 日本学術振興会：科学研究費助成事業 基盤研究(B)
    Date (from‐to) : 2020/04 -2025/03 
    Author : 堀田 晴美; 重本 和宏
     
    高齢者のサルコペニア(骨格筋萎縮)予防のために「口から食べる」重要性が指摘されている。しかし、その理由はよくわかっていない。嚥下を誘発する咽頭への機械的刺激が、自律神経を介して甲状腺からのホルモンの分泌を促進するという現象を、私たちは新たに見出した。本研究では、この成果を発展させ、口や喉からの情報が、自律神経を介して骨格筋の維持をもたらすとの仮説を確かめるための基礎研究をおこなう。本研究の成果は、高齢者のサルコペニアを予防する新しい方法の開発につながるものである。 昨年度の研究により、咽頭刺激によって筋交感神経活動が高まり、骨格筋血流に影響を与えることが明らかになった。そうなると、その筋交感神経の活動は、骨格筋のはたらき（つまり筋収縮）にどのような意味があるか、疑問が生じる。そこで今年度は、骨格筋収縮力に対する筋交感神経の役割を調べた。 一側下肢を固定し、アキレス腱を露出して張力計に接続し筋張力を測定した。下腿三頭筋を支配する脛骨神経を、埋め込み電極を使って電気刺激した。刺激には、太い運動神経（I群線維）のみを興奮させる弱い電流を用いた。間欠的に高頻度刺激を加えることで、歩行時のようなリズミカルな筋収縮を誘発した。骨格筋が収縮すると、収縮筋からの細い求心性神経（Ⅲ群・Ⅳ群線維）が興奮して、反射性に心血管系の交感神経が興奮することが古くから知られている。脛骨神経刺激により下腿三頭筋が収縮すると、その時反射性に下肢の筋交感神経も興奮すると推測される。下肢への交感神経の専用経路である腰部交感神経幹を切断して、その切断前後で坐骨神経刺激による前脛骨筋の収縮力を比較することで、交感活動の筋収縮力への関与を明らかにした。
  • Japan Society for the Promotion of Science：KAKENHI, Grants-in-Aid for Scientific Research
    Date (from‐to) : 2020/04 -2025/03 
    Author : Harumi Hotta; Hiroshi Nishimune, Kazuhiro Shigemoto
     
    高齢者のサルコペニア(骨格筋萎縮)予防のために「口から食べる」重要性が指摘されている。しかし、その理由はよくわかっていない。嚥下を誘発する咽頭への機械的刺激が、自律神経を介して甲状腺からのホルモンの分泌を促進するという現象を、私たちは新たに見出した。本研究では、この成果を発展させ、口や喉からの情報が、自律神経を介して骨格筋の維持をもたらすとの仮説を確かめるための基礎研究をおこなう。本研究の成果は、高齢者のサルコペニアを予防する新しい方法の開発につながるものである。 昨年度までの研究で、ラット後肢の筋力の維持には、筋収縮をきっかけとした交感神経の反射性活動が寄与することを明らかにした。今年度は、筋収縮と交感神経の間のこのフィードバック機構が、老化によって低下する可能性を調べた。その結果、老化ラットでは筋力における交感神経の寄与の程度が、予想通り、若いラットよりも少なくなっていることがわかった。その一方で、老化ラットでは運動神経とは関係ない交感神経性の筋緊張がおこりやすくなっていることを見つけた。つまり、老化ラットの交感神経では、運動神経をサポートする働きが衰えるだけでなく、単独で筋緊張をおこすようになる。これらの変化は、老化による筋力低下と運動機能の低下の原因の一端を説明する。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
    Date (from‐to) : 2019/04 -2022/03 
    Author : Shigemoto Kazuhiro
     
    The loss of muscle strength and motor function associated with sarcopenia is expected to be accompanied by qualitative changes in muscle due to aging but has not yet been clearly defined pathologically. Elucidation of the mechanism of sarcopenia based on pathological evidence is necessary for the development of scientifically based early diagnosis and assessment methods. Using aging MusColorTM mice developed by the applicant, we found characteristic myofiber type changes. We also established a new research method by establishing the MusColorTM muscle cell line. This study successfully defined the pathology of early qualitative changes in sarcopenia in combination with the results of the morphological changes and functional decline of muscle mitochondria and their mechanisms during aging.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
    Date (from‐to) : 2016/04 -2019/03 
    Author : Shigemoto Kazuhiro
     
    In the process leading to sarcopenia and muscle atrophy, unidirectional skeletal muscle fiber type change (sarcopenia: fast muscle → slow muscle) occurs. We are conducting research with the aim of clarifying the causal relationship between muscle fiber type changes (metabolic changes) and the mechanism of sarcopenia and muscle atrophy, and linking it to the development of methods for preventing and treating sarcopenia and muscle atrophy. Each muscle fiber type has its own energy metabolic properties, and in this study different metabolic properties of mice. We have developed MusColor mice that allow all four types of muscle fiber types that have alive to be distinguished alive with different fluorescent proteins. Using this MusColor technology, we have found in vivo factors that induce muscle fiber type changes (metabolism conversion) and studied the mechanism.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2015/04 -2018/03 
    Author : Zhou Heying; Shigemoto Kazuhiro; Shinkai shoji
     
    Our research aim is to develop a potential predictor for age-related muscle atrophy, also named as sarcopenia, which is one of the most important causes of functional decline and has been associated with reduced quality of life in older adults. We analyzed a membrane protein A of postsynapse in human subjects. The protein A is required for the maintenance of neuromuscular junctions and reflects neuromuscular synaptic activity. In our senior study, protein A concentrations were not affected by muscle mass, neither strength, nor mobility in the long-term. However, serum protein A levels are positively correlated with Maximum oxygen consumption, daily physical activity, and the number of steps. Furthermore, blood levels of protein A increased significantly after a three-month exercise intervention in community-dwelling older adults. Consistent with this result of our study, protein A has been shown to reflect at least in part physical performance in aged people.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)
    Date (from‐to) : 2011/04 -2016/03 
    Author : Kimura Yurika; KITAMURA KEN; IKEZONO TETSURO; SHIGEMOTO KAZUHIRO; SAWABE MOTOJI; KUBO SACHIHO; KOBAYASHI HITOME
     
    1. Introduction of Laser microdissection for the analysis of human temporal bone pathology: We succeeded in the detection of mRNA expression of COCH in spiral ligaments and SLC26A5 in outer hair cells. 2. Presbycusis and cochlin : Distribution of cochlin imunostaining is changed with aging. 3. Influence of mitochondria DNA mutation in the cochlear lateral wall: in the case of mt3243 point mutation, the ratio of mtDNA 3243 mutation was low but atrophy of stria vascular was severe. Because stria vascularis requires high energy and mitochondrial rich organ, it is weak to the mutation even at low level.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research
    Date (from‐to) : 2013/04 -2015/03 
    Author : SHIGEMOTO Kazuhiro
     
    Sarcopenia impairs activity of daily living of aged people. For the early prevention or treatment of such conditions, it is required to understand the pathogenesis and invent effective therapies. In this study, we will elucidate the metabolic changes in skeletal muscle during aging and establish the new technologies for developing innovative preventive and therapeutic methods by remodleing the metabolism.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
    Date (from‐to) : 2012/04 -2015/03 
    Author : SHIGEMOTO KAZUHIRO; MORI Shuuichi; EDAMATSU Midori; MIYAZAKI Tsuyoshi; KOSHI Katsuo; KONISHI Tetsuro
     
    1.Some patients with myasthenia gravis (MG) caused by antibodies against muscle-specific kinase (MuSK; MuSKMG) apparently do not respond to immunosuppressive therapy and rapidly progress to life-threatening muscle atrophy. In addition, long-term administration of corticosteroids, which are first-line treatment of MG, is frequently responsible for severe adverse effect. We found that rapamycin treatment suppressed occurrence of MG-like phenotypes, including weight loss and significant decrement of compound muscle action potentials with the histological evidence. Rapamycin may be useful as an immunomodulation drug of MG. 2. We generated a murine model of MG caused by anti-Lrp4 antibodies via active immunization of LRP4 protein, providing the evidence for the pathogenicity of anti-Lrp4 antibodies. We expect our approach and the model will be of value to the MG research community, helping to accelerate development of therapeutic candidates for clinical translation.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Innovative Areas (Research a proposed research project)
    Date (from‐to) : 2009 -2011 
    Author : SHIGEMOTO Kazuhiro; KUBO Sachiho; MIYAZAKI Tsuyoshi; YAMADA Shigeru
     
    We found that MuSK molecules, which are expressed at post synaptic membrane of NMJs, mediates unknown retrograde signaling which regulate presynaptic functions. We generated mouse expressed-genes database for atrophy-induced muscles to find the retrograde-signaling molecules.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2009 -2011 
    Author : SHIGEMOTO Kazuhiro; KONISHI Tetsuro
     
    We generated a new animal model in which 100% of mice synchronously develop experimental animal model of myasthenia gravis after immunization with MuSK protein. Our model provides a valuable platform from which to evaluate the role of MuSK signaling in NMJ maintenance and the immune mechanisms and pathophysiology of MuSK-MG, and we propose that 3, 4-DAP may be effective as a symptomatic therapy.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2006 -2007 
    Author : SHIGEMOTO Kazuhiro; UEDA Norifumi; MATSUDA Seiji
     
    We have provided the evidence that active immunization with MuSK protein reproduces myasthenia gravis in animals. Next we focus on how MuSK antibodies cause MG. The pathogenic roles of MuSK antibodies in MG have been questioned as the number of AChRs is not reduced and complement is not deposited at the NMJ of biceps brachii muscles MuSK-positive patients with MG. The mechanisms of MG caused by AChR antibodies are well delineated, but the revealed mechanisms are not able to simply apply to MG with MuSK antibodies. MuSK antibodies have been identified as predominantly IgG4 subclass, which does not activate complement. We found that agrin-induced clustering of AChR was strongly blocked in the presence of MuSK antibodies, whereas absorption of the antibodies with purified MuSK products prevented this blocking effect. These results showed that the MuSK antibodies effectively inhibited the formation of agrin-induced AChR clustering. Intriguingly, the monovalent Fab fragments of MuSK antibodies from rabbits with EAMG also inhibited AChR clustering by agrin on C2C12 cells, indicating that complement-mediated mechanisms are not necessarily required for such inhibition. We then examined the reduced expression of AChR at NMJ in soleus muscles of paretic and normal rabbits by fluorescence microscopy. In addition, the structure of NMJ in our paretic rabbits, as well as the size and branching of the motor terminals, were significantly reduced. Electron microscopic observations of NMJ in rabbits with EAMG induced by injection of MuSK protein demonstrated a significant loss of complexity of convoluted synaptic folds but no destruction, and EAMG model cited here resembles the phenotype of humans with MG and MuSK antibodies. Our results showed that MuSK antibodies inhibit both anterograde and retrograde signals required for maintaining the synaptic structures in mature NMJ.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2004 -2005 
    Author : SHIGEMOTO Kazuhiro; MOMINOKI Katsumi; MATSUDA Seiji; MARUYAMA Naoki; KUBO Sachiho
     
    Muscle-specific kinase (MuSK) is critical for the synaptic clustering of nicotinic acetylcholine receptors (AChR) and plays multiple roles in the organization and maintenance of neuromuscular junctions (NMJ). MuSK is activated by agrin, which is released from motoneurons, and induces AChR clustering at the postsynaptic membrane. Although autoantibodies against the ectodomain of MuSK have been found in a proportion of patients with generalized myasthenia gravis (MG), it is unclear whether MuSK autoantibodies are the causative agent of generalized MG. In the present study, rabbits immunized with MuSK ectodomain protein manifested MG-like muscle weakness with a reduction of AChR clustering at the NMJ. The autoantibodies activated MuSK and blocked AChR clustering induced by agrin or by mediators that do not activate MuSK. Thus, MuSK autoantibodies rigorously inhibit AChR clustering mediated by multiple pathways, an outcome that broadens our general comprehension of the pathogenesis of MG.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2002 -2003 
    Author : SHIGEMOTO Kazuhiro; MARUYAM Naoki
     
    We firstly identified anti-MuSK autoantibodies in generalized myasthenia gravis(MG) with detectable AChR autoantibodies(seropositive MG) and reported in Nurology(in press, 2004). Previously, Hoch et al. found a novel antigen, MuSK in MG without detectable AChR autoantibodies(seronegative MG) in 2001. Therefore we could provide a new scope for the functions of MuSK and the molecular pathogenesis of generalized MG caused by the MuSK autoaintibodies. Next we could produce the MuSK autoantibodies by immunization of MuSK proteins in rabbits in which a MG-like muscular weakness had been induced. We then found clear-cut evidence that these MuSK antibodies specifically inhibited the AChR clustering response to all known stimuli including those of the agrin-independent pathways. Agrin induces AChR clustering by activation of MuSK, whereas agrin-independent stimuli did not. That is, the MuSK autoantibodies rigorously inhibited AChR clustering mediated by multiple pathways, an outcome that broadens general comprehension of MG's pathogenesis(submitted for publication in 2004). Finally, we prepared a large amount of MuSK protein for the analysis of protein structure. We are now screening the optimal conditions for the crystallization to analyze the structure using a synchrotron(Spring-8) in Harima-riken. In addition, we are now analyzing MuSK-lacZ-knock-in mice to elucidate the MuSK functions in the organisms.
  • 日本学術振興会：科学研究費助成事業 重点領域研究
    Date (from‐to) : 1997 -1997 
    Author : 近藤 郁子; 重本 和宏
     
    パーキンソン病(Parkinson's disease:PD)はアルツハイマー病(Alzheimer's disease:AD)に次いで頻度の高い中高齢者の神経難病である。原因は不明であるが、特定の遺伝性要因を持つ人々に、加齢とともに生活習慣を含む環境因子が作用して発病にいたる多因子疾患に位置づけられている。本研究では環境因子と遺伝性素因を明らかにするために、香川県の中核病院に通院中のPD患者とその地域の同年齢の健康者集団におけるPD発症候補遺伝子の解析を行った。 研究協力要請に際し、十分な同意を得て血液を採取しDNAを抽出した。候補遺伝子として、ADの発症促進因子とされるα-antichymotrypsinのDNA多型(A、T遺伝子型)を用いた。また、常染色体優性遺伝性PDの原因遺伝子として報告されたα-synuclein遺伝子の全エキソンのDNA変異を検索した。その結果、ADの発症因子とされるα-anti chymotrypsinのA型遺伝子の頻度はPD患者でも健常者に比べて有意に高く(P<0.05),A型遺伝子のホモ接合体はT型遺伝子のホモ接合体比べて焼く3.36倍、AとT型遺伝子型の保因者(ヘテロ接合体)に比べて2.18倍の相対発症危険率を示した。しかし、α-synuclein遺伝子の解析では、特発性PD患者には優性型PDにみられて遺伝子変異は同定されなかった。さらに、全部のエキソン部分のDNA変異解析では3つのDNA変異が同定されたが、健常者のも同じ頻度に検出される遺伝子多型であった。以上の結果、PDの発症にはADと共通の遺伝性素因の関わる機序が存在することが示唆された。また、優性遺伝性PDの原因は最も頻度の高い一般的な特発性PDの原因にはならないことが明らかになった。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for General Scientific Research (B)
    Date (from‐to) : 1990 -1991 
    Author : TAKEMORI Toshitada; TOKUHISA Takeshi; MIZUGUCHI Junichiro; OHNISHI Kazuo; KIMOTO Hiroshi
     
    We have estabilished immature B cell clones, 46-6, 46-11, 46-12 and 46-13, generated from a COMM'on precursor cell transformed with a temperature sensitive(ts)mutant of Abelson murine leukemia virus(A-MuLV). All members of clones essentially became surface Ii chain positive (mum^+) pre B cells as a result Of V_H gene replacement when they were cultured at nonpermissive temperature. By using this system, we have observed that various intrachromosomal circular DNAs were generated in a clone 46-6 cultured at high temperature. The structural analysis of the isolated circular DNA clones provided the evidence that V_H gene replacement occurs by intramolecular DNA deletion as seen in V-(D)-J joining. Sequence analysis of a large number of DNA clones containing a functional heavy chain variable, diversity and joining complex generated by VH gene replacement in the progeny derived from a common precursor cell transformed with a ts A-MuLV indicates that endogenous V_H gene replacement in vitro generates Ig gene joints distinct from those generated by usual V_H to DJ_H joining. Such joints keep the 5mer CAAGA at the 3'end of the donor V_H segment and lack a recognizable D segment, as can be also seen in vivo. The results suggest that V_H gene replacement participates in generating V_H region diversity in vivo as previously postulated. During the joining process, a unique V_H gene was selected in all progeny cells, together with a single A nucleotide dominantly added to the junctional boundaries. A previously unreported B cell specific gene, designated 8HS-20, was isolated from the cDNA library of a pre-B cell clone by subtraction and differential hybridization. This gene is selectively expressed as a 0.7kb transcript in pre-B and bone marrowderived B cell lines and the same size transcript is also found in bone marrow and, albeit at low levels, in spleen. The deduced amino acid sequence of 8HS-20 cDNA displayed homology to a B cell specific gene, VpreB-l, and members of the immunoglobulin super gene family including Vlambda, Vkappa, VH, TCRValpha, Vbeta and CD8. Biochemical analysis using purified antiserum against 8HS-20 oligopeptides indicates that the gene encodes proteins with MW of 13.5, 14, 15, 5 and 16kDa, which associate with mu chains in pre-B cell lines, and that these molecules are concomitantly expressed with VpreB-l and lambda5 gene products in the same cell lines.
  • 日本学術振興会：科学研究費助成事業 重点領域研究
    Date (from‐to) : 1990 -1990 
    Author : 竹森 利忠; 谷山 忠義; 大西 和夫; 重本 和宏
     
    我々が単離したAbelsonマウス白血病ウイルス由来温度感受性変異株を用いたトランスフォ-メ-ションにより、胎児胸腺よりThyー1^ー/Scaー1^+/ILー2R^+の表現型を示す幼若造血細胞5,6,12,19,33,42を、またThyー1^+/Scaー1^+/ILー2R^+の表現型を示すクロ-ンC1、C10ー7を単離した。33,42はILー1の刺激により形態学的にマクロファ-ジへ、更に6,33,42は胎児胸腺組織培養により形態学的にマスト細胞へ分化した。19はマクロファ-ジのみに分化した。C1およびC10ー7はILー1の刺激によりマクロファ-ジへ分化し、アクセサリ-細胞を除去した T細胞の増殖をConAの存在下および非存在下で増殖を支持することが明かとなった。これらのクロ-ンにおける他の系への分化能をサイトカインあるいは造血支持細胞存在下での実験系で検討したが、リンパ球、白血球系への分化は認められなかった。一方分化前のC10ー7細胞表面抗原に対するモノクロナ-ル抗体3F7ーA1,3A9ーD1を作製し、抗原の性状およびこの抗原を発現する細胞の性状および動態を確認したところ、成熟組織ではBリンパ球系の細胞にこの抗原が選択的に発現され、また3F7ーA1抗原発現に関して、B細胞発生の過程で幼若B細胞は抗原陽性と陰性の2つの亜集団に分別されることが示唆された。一方胎生初期胸腺にはこれらの抗原を発現する細胞は高頻度に存在するものの、成熟胸腺では殆ど認められない。また数回の実験に関して特に胎児組織では、胎生につれて3F7ーA1抗原の発現が複雑に変動することが示唆され、今後更にその発現意義を詳細に検討する必要性が認められた。3F7ーA1および3A9ーD1抗原はそれぞれ50ー60kdおよび40kdの蛋白質分子を認識することが示唆されており、また各組織における発現様式により新しい造血細胞表面抗原であると考えられる。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for General Scientific Research (B)
    Date (from‐to) : 1988 -1989 
    Author : TAKEMORI Toshitada; SHIGEMOTO Kazuhiro; TAGAWA Masatoshi
     
    1. Isolation and characterization of new genes expressed In B lineage cells. We have succeeded in isolating new genes, 8HS-15 and 8HS-20, from Abelson murine leukemia virus (A-MuLV) transformed pre-B lymphoma using subtraction and differential hybrydization techniques. 8HS-20 is expressed as 0.75kb. transcript in B lineage cells and the level of the message is significantly augmented in pre-B lymphoma when compared to that in normal B cells in the spleen. 8HS-15 is expressed as 1.5kb transcript in A-MuLV transformed pre-B cells and 3.Okb transcript in T lineage cells, fibroblast, and tissues. Sequence analysis of 8HS-20 cDNA clone reveals a long open reading frame, capable of encoding a protein of 123 amino acids with an unprocessed molecular weight of 13k. The predicted protein of 8HS-20 shares 42% homology with human Vlambda and 38% homology with another pre B specific gene, Vpre B-1. We prepared polyclonal antisera for synthesized peptides of 8HS-20 and used them to probe total cell lysates of a mature B cell clone WEHI 231 transfected with or without 8HS-20 cDNA clone in expression vector. The antisera specifically immunoprecipitated 10 and 16kd molecules in WEHI 231 transfected with 8HS-20, but not in a wild type of WEHI 231. The analysis of immunoprecipitation of a virgin B cell clone, CYG34 revealed that the molecule encoded by 8HS-20 appeared to be associated with a small fraction of mu chains, but not with those linked to k light chains. As observed in WEHI 231, the molecule encoded by 8HS-20 was associated with unknown 16kd molecule in CYG34. 2. Analysis of small polypeptides associated with Ii chain and their role in signal transduction We have identified the complexes of polypeptides associated with IL chains of pre B cell lines. Most of these polypeptides were continuously synthesized and associated with IL chains in virgin B cell lines, although some of them scarcely bound to the mk dimer or IL2lc2 tetramer concomitantly present in the same clone or population. However, they were no longer detectable in mature B cells with rare exceptions. Cross-linking of lam chains on the surface of pre B cells resulted in an increase in intracellular free Ca2, indicating that the itm chain complex on the surface of pre B cell lines acted as a signal transduction molecule. However, the receptor cross linkage of pre B cell lines did not induce the increased inositol phospholipid metabolism usually observed in virgin and mature B cell lines. These results suggest that, during the differentiation from,pre B to mature B cells, the cells express two types of Ii chain complexes which exhibit different structures as a whole and possess different signal transducing capacities. We have identified the complexes of polypeptides associated with mu chains of pre B cell lines. Most of these polypeptides were continuously synthesized and associated with mu chains in virgin B cell lines, although some of them scarcely bound to the mk dimer or mu2kappa tetramer concomitantly present in the same clone or population. However, they were no longer detectable in mature B cells with rare exceptions. Cross-linking of mum chains on the surface of pre B cells resulted in an increase in intracellular free Ca^<2+>, indicating that the mum chain complex on the surface of pre B cell lines acted as a signal transduction molecule. However, the receptor cross linkage of pre B cell lines did not induce the increased inositol phospholipid metabolism usually observed in virgin and mature B cell lines. These results suggest that, during the differentiation from pre B to mature cells, the cells express two types of mu chain complexes which exhibit different structures as a whole and possess different signal transducing capacities. 3. Isolation of differentiation-inducible hematopoletic cell clones. We have established immature hematopoietic clones from fetal thymus by transforming with a temperature sensitive (ts) mutant of A-MuLV in vitro. When one of the clone (B6-24) was intrathymically injected, a small fraction of the cells differentiated into the cells bearing T or B lymphocytes markers. Whereas, the stimulation by recombinant interleukin-1 in vitro made this clone differentiate into macrophage-like cells. This effect is essentially replaced by CAMP analogue and its inducing reagents. In addition to B6-24, we have established other immature hematopoietic cell clones exhibiting the phenotypes of Thyl-/Sca-1^+/lineage marker (lin^-), Thy1^-/Sca1^+/CD^<4+>/B220^+, Thy1^+/Sca-1^+/CD4^+/B220^+. We are analyzing their potentiality to differentiate into multi lineage cells.
  • 日本学術振興会：科学研究費助成事業 がん特別研究
    Date (from‐to) : 1988 -1988 
    Author : 竹森 利忠; 重本 和宏
     
    細胞がん化は、正常細胞における増殖・分化関連分子の遺伝子レベルにおける質的・量的な変動と、それに伴うシグナル伝達機構の脱制御により誘導されることが明らかになりつつある。しかしこのように脱制御されて核内へ伝達されるシグナルが、それに対応するどのような一連の遺伝子発現に、どのような影響をおよぼすかについては明らかでない。この問題の解決のための一つのアプローチとして、ウイルスがん遺伝子発現を契機に、その発現様式を変動させる細胞遺伝子の構造と機能を解析することは重要と思われる。我々は温度感受性Abelsonマウス白血病ウイルス感染幼若Bリンフォーマに分化を導入し、分化前後にその発現様式を変動させる遺伝子8HS-15.を単離した。この遺伝子発現は、B細胞以外の組織・細胞では3・5Kbの、B細胞では約1・8Kbのサイズのメッセージとして発現され、Bリンフォーマでの発現量は著明に増強する。この遺伝子の塩基配列に相当する配列はGen Bankのdata baseには存在しない。一方、同一のシステムを用いて幼若Bリンフォーマに特異的に発現する遺伝子8HS-20を単離した。この遺伝子は精巣で1・2Kb、T細胞および他の組織では1・0Kb、B細胞では0・7Kbのメッセージとして発現される。B細胞に特異的な0・7Kbのメッセージの発現量は幼若Bリンフォーマ株で、正常脾臓B細胞あるいは成熟B細胞株のそれと比較すると、30-40倍に増強している。得られた遺伝子クローン(0・4Kb)の塩基配列から、この遺伝子の塩基配列と同一なもの、あるいはhomologyの高い塩基配列を有する遺伝子はGen Bankのdata baseには認められなかった。
  • 日本学術振興会：科学研究費助成事業 奨励研究(A)
    Date (from‐to) : 1987 -1987 
    Author : 重本 和宏

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