Researchers Database

jimbo eriko

    PediatricsPediatricMedicine Assistant Professor
Last Updated :2021/12/07

Researcher Information

URL

J-Global ID

Research Interests

  • 言語障害   脳・神経   超音波音声   マウス   シグナル伝達   シナプス   発酵食品   接着蛋白   D-アラニン   Par-3   旨味   RA175   進化   遊離アミノ酸   FOXP2   Cadm1   魚醤油   自閉症   

Research Areas

  • Life sciences / Neuroanatomy and physiology
  • Life sciences / Marine/Aquatic life sciences

Academic & Professional Experience

  • 2012  Jichi Medical UniversitySchool of Medicine講師

Published Papers

  • Yuko Tanabe, Akira Shiota, Yoriko Kouroku-Murakami, Eriko Fujita-Jimbo, Koko Urase, Kana Takahashi, Yoshihiro Mezaki, Haruki Senoo, Takashi Momoi
    NEUROSCIENCE LETTERS 576 1 - 5 0304-3940 2014/07 [Refereed][Not invited]
     
    Src kinase-associated phosphoprotein 2 (Ra70/scap2), which was originally isolated as a retinoic acid (RA)-induced gene, associates with molecules that modulate integrin-survival signals. Although RA is essential for vertebrate organogenesis in the posterior region, little is known about the biological role of RA70/Scap2 during development. In the present study, we demonstrate that Ra70/scap2 mRNA is temporally expressed during the RA-induced neuronal differentiation of P19 embryonic carcinoma cells. Homozygous knockout mice in which the Ra70/scap2 gene was replaced with LacZ exhibited embryonic lethality, while heterozygous mice displayed preferential expression of LacZ in posterior neural tissues, including the neural tube and hindbrain during development (E7.5-11.5), but not the forebrain. Ra70/scap2 was expressed in the ependymal layer and ventricular zone in the neural tube, where neuroepithelial cells and neuroblasts with proliferation capacity are localized, respectively. Thus, RA70/Scap2 may be necessary for RA-induced neuronal differentiation from the posterior neuroectoderm. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
  • Eriko Fujita-Jimbo, Takashi Momoi
    NEUROSCIENCE LETTERS 566 162 - 166 0304-3940 2014/04 [Refereed][Not invited]
     
    The R553H mutation has been found in the FOXP2 gene of patients with speech-language disorder. Foxp2(R552H) knock-in (KI) mice exhibit poor dendritic development of Purkinje cells in the cerebellum and impaired ultrasonic vocalization (USV), which is related to human speech and language; compared with wild-type mice, heterozygous Foxp2(R552H)-KI pups exhibit the reduced number of whistle-type USVs and the increased short-type ones, while homozygous pups exhibit only click-type USVs but no whistle-type or short-type ones. To make clear the relationship between the role of Foxp2 in the cerebellum and whistle-type USVs activity, we prepared transgenic (Tg) mice specifically expressing human FOXP2-myc in cerebellum (Pcp2-FOXP2-myc-Tg mice) by using purkinje cell protein-2 (Pcp2) promoter. FOXP2-myc expression in the cerebellum increased the relative numbers of whistle-type USVs in the heterozygous Foxp2(R552H)-KI pups and recovered their USVs but did not in the homozygous ones. Foxp2 in the cerebellum may pertain to the brain network engaged in whistle-type USVs activities including modification, but not their production. There may be common molecular contribution of Purkinje cells to human FOXP2-mediated speech-language and mouse Foxp2-mediated USVs. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
  • Ayumi Matsumoto, Makoto Mizuno, Nanako Hamada, Yasuyuki Nozaki, Eriko F. Jimbo, Mariko Y. Momoi, Koh-ichi Nagata, Takanori Yamagata
    PLOS ONE 9 (3) e92695  1932-6203 2014/03 [Refereed][Not invited]
     
    Interstitial deletion of 12q21 has been reported in four cases, which share several common clinical features, including intellectual disability (ID), low-set ears, and minor cardiac abnormalities. Comparative genomic hybridization (CGH) analysis using the Agilent Human Genome CGH 180K array was performed with the genomic DNA from a two-year-old Japanese boy with these symptoms, as well as hypoplasia of the corpus callosum. Consequently, a 14 Mb deletion at 12q21.2-q21.33 (nt. 77 203 574-91 264 613 bp), which includes 72 genes, was detected. Of these, we focused on LIN7A, which encodes a scaffold protein that is important for synaptic function, as a possible responsible gene for ID, and we analyzed its role in cerebral cortex development. Western blotting analyses revealed that Lin-7A is expressed on embryonic day (E) 13.5, and gradually increases in the mouse brain during the embryonic stage. Biochemical fractionation resulted in the enrichment of Lin-7A in the presynaptic fraction. Suppression of Lin-7A expression by RNAi, using in utero electroporation on E14.5, delayed neuronal migration on postnatal day (P) 2, and Lin-7A-deficient neurons remained in the lower zone of the cortical plate and the intermediate zone. In addition, when Lin-7A was silenced in cortical neurons in one hemisphere, axonal growth in the contralateral hemisphere was delayed; development of these neurons was disrupted such that one half did not extend into the contralateral hemisphere after leaving the corpus callosum. Taken together, LIN7A is a candidate gene responsible for 12q21-deletion syndrome, and abnormal neuronal migration and interhemispheric axon development may contribute to ID and corpus callosum hypoplasia, respectively.
  • Mari Saito, Takanori Yamagata, Ayumi Matsumoto, Yusuke Shiba, Masako Nagashima, Shuhei Taniguchi, Eriko Jimbo, Mariko Y. Momoi
    BRAIN & DEVELOPMENT 36 (1) 64 - 69 0387-7604 2014/01 [Refereed][Not invited]
     
    Deletion of the monoamine oxidase (MAO)-A and MAO-B was detected in two male siblings and in their mother. The approximately 800-kb deletion, extending from about 43.0 MB to 43.8 MB, was detected by array comparative genomic hybridization analysis. The MAOA and MAOB genes were included in the deletion, but the adjacent Norrie disease gene, NDP, was not deleted. The boys had short stature, hypotonia,,severe developmental delays, episodes of sudden loss of muscle tone, exiting behavior, lip-smacking and autistic features. The serotonin levels in their cerebrospinal fluid were extremely elevated. Another set of siblings with this deletion was reported previously. We propose recognition of MAOA/B deletion syndrome as a distinct disorder. (C) 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
  • Ayumi Matsumoto, Mari Kuwajima, Kunio Miyake, Karin Kojima, Naomi Nakashima, Eriko F. Jimbo, Takeo Kubota, Mariko Y. Momoi, Takanori Yamagata
    JOURNAL OF HUMAN GENETICS 58 (11) 755 - 757 1434-5161 2013/11 [Refereed][Not invited]
     
    The ribosomal protein S6 kinase, 90 kb, polypeptide 3 gene (RPS6KA3) is responsible for Coffin-Lowry syndrome (CLS), which is characterized by intellectual disability (ID) and facial and bony abnormalities. This gene also affects nonsyndromic X-linked ID and nonsyndromic X-linked ID without bony abnormalities. Two families have been previously reported to have genetic microduplication including RPS6KA3. In the present study, we used array-comparative genomic hybridization (CGH) analysis with Agilent Human genome CGH 180K and detected a 584-kb microduplication spanning 19.92-20.50 Mb of Xp22.12 (including RPS6KA3) in the members of one family, including three brothers, two sisters, and their mother. The 15-year-old male proband and one of his brothers had mild ID and localization-related epilepsy, whereas his other brother presented borderline intelligence quotient (IQ) and attention-deficit-hyperactivity disorder (ADHD). One sister presented pervasive development disorder (PDD). Analysis of this family suggests that RPS6KA3 duplication is responsible for mild ID, ADHD, and localization-related epilepsy, and possibly for PDD.
  • Yuko Tanabe, Eriko Fujita, Yukiko K. Hayashi, Xinran Zhu, Hermann Lubbert, Yoshihiro Mezaki, Haruki Senoo, Takashi Momoi
    CELL BIOLOGY INTERNATIONAL 37 (7) 731 - 736 1065-6995 2013/07 [Refereed][Not invited]
     
    RA175/SynCAM1/Cadm1 (Cadm1), a member of the immunoglobulin superfamily, is a synaptic cell adhesion molecule that has a PDZ-binding motif at the C-terminal region. It promotes the formation of presynaptic terminals and induces functional synapses in the central nervous system. Cadm1-deficient (knockout [KO]) mice show behavioral abnormalities, including excessive aggression and anxiety, but do not show any symptoms of neuromuscular disorder, although neuromuscular junctions (NMJs) have structures similar to synapses. We have examined the expression of members of the Cadm family in the mouse muscle tissues. Cadm4 and Cadm1 were major components of the Cadm family, and Cadm3 was faintly detected, but Cadm2 was not detected by RT-PCR. Cadm4 as well as Cadm1 colocalized with alpha-bungarotoxin at the NMJs and interacted with the multiple PDZ domain protein Mupp1. Cadm4 was expressed in Cadm1-KO mice and might compensate for Cadm1 loss through interactions with Mupp1.
  • Eriko Fujita-Jimbo, Zhi-Ling Yu, Hong Li, Takanori Yamagata, Masato Mori, Takashi Momoi, Mariko Y. Momoi
    PLOS ONE 7 (12) e51155  1932-6203 2012/12 [Refereed][Not invited]
     
    Little is known about the molecular pathogenesis of Autism spectrum disorder (ASD), a neurodevelopmental disorder. Here we identified two mutations in the G-protein-coupled receptor 37 gene (GPR37) localized on chromosome 7q31-33, called the AUTS1 region, of ASD patients; 1585-1587 ttc del (Del312F) in one Japanese patient and G2324A (R558Q) in one Caucasian patient. The Del312F was located in the conserved transmembrane domain, and the R558Q was located in a conserved region just distal to the last transmembrane domain. In addition, a potential ASD-related GPR37 variant, T589M, was found in 7 affected Caucasian men from five different families. Our results suggested that some alleles in GPR37 were related to the deleterious effect of ASD. GPR37 is associated with the dopamine transporter to modulate dopamine uptake, and regulates behavioral responses to dopaminergic drugs. Thus, dopaminergic neurons may be involved in the ASD. However, we also detected the Del321F mutation in the patient's unaffected father and R558Q in not only an affected brother but also an unaffected mother. The identification of unaffected parents that carried the mutated alleles suggested that the manifestation of ASD was also influenced by factors other than these mutations, including endoplasmic reticulum stress of the mutated proteins or gender. Our study will provide the new insight into the molecular pathogenesis of ASD.
  • Eriko Fujita, Yuko Tanabe, Beat A. Imhof, Mariko Y. Momoi, Takashi Momoi
    JOURNAL OF NEUROCHEMISTRY 123 (5) 886 - 894 0022-3042 2012/12 [Refereed][Not invited]
     
    Mutations in the synaptic adhesion protein CADM1 (RA175/SynCAM1) are associated with autism spectrum disorder (ASD), a neurodevelopmental disorder of uncertain molecular origin. Cadm1-knock out (KO) mice exhibit smaller cerebella with decreased number of synapse of Purkinje cells and some ASD-like symptoms, including impaired ultrasonic vocalization. In this study, we examined the alteration of the Cadm1 synaptic complex in the mouse cerebellum at post-natal stages. The C-terminal peptide of Cadm1 associated with Mupp1 at PSD-95/Dlg/ZO-1 (PDZ)(1-5), a scaffold protein containing 13 PDZ domains, which interacted with gamma-aminobutyric acid type B receptor (GABBR)2 at PDZ13, but not with PSD-95. The GABBR2 was detected in a set of proteins interacting with Cadm1 C-terminal. Cadm1 colocalized with Mupp1 and GABBR2 on the dendrites of Purkinje cells in the molecular layers of the developing cerebellum and on the dendrites of hippocampal neurons cultured in vitro. These observations suggest that the Cadm1 synaptic receptor complex, including Mupp1GABBR2, is located on the dendrites of Purkinje cells. The amount of GABBR2 protein, but not mRNA, was increased in the cerebella of Cadm1 KO mice, suggesting that lack of Cadm1 does not affect transcription of GABBR2, but may stabilize the Mupp1GABBR2 complex; the Mupp1GABBR2 interaction may be stabilized by conformational change in Mupp1 or association with other adhesion molecules and by anchorage to the post-synaptic membrane. Up-regulation of GABBR2 in the cerebellum in the absence of CADM1 may be associated with ASD pathogenesis.
  • Yuko Tanabe, Yuji Fujiwara, Ayumi Matsuzaki, Eriko Fujita, Tadashi Kasahara, Shigeki Yuasa, Takashi Momoi
    JOURNAL OF NEUROCHEMISTRY 122 (1) 72 - 80 0022-3042 2012/07 [Refereed][Not invited]
     
    J. Neurochem. (2012) 122, 7280. Abstract FOXP2, a forkhead box-containing transcription factor, forms homo- or hetero-dimers with FOXP family members and localizes to the nucleus, while FOXP2(R553H), which contains a mutation related to speech/language disorders, features reduced DNA binding activity and both cytoplasmic and nuclear localization. In addition to being a loss-of-function mutation, it is possible that FOXP2(R553H) also may act as a gain-of-function mutation to inhibit the functions of FOXP2 isoforms including FOXP2Ex10+ lacking forkhead domain. Foxp2(R552H) knock-in mouse pups exhibit impaired ultrasonic vocalization and poor dendritic development in Purkinje cells. However, expressions of Foxp2 isoforms in the developing Purkinje are unclear. The appearance of apical cytoplasmic swelling (mitochondria-rich regions that are the source of budding processes) correlates with dendritic development of Purkinje cells. In the present study, we focused on Foxp2 isoforms localizing to the apical cytoplasmic swelling and identified two isoforms lacking forkhead domain: Foxp2Ex12+ and Foxp2Ex15. They partly localized to the membrane fraction that includes mitochondria. Foxp2Ex12+ mainly localized to the apical cytoplasmic swelling in early developing Purkinje cells at the stellate stage (P2P4). Mitochondrial localization of Foxp2Ex12+ in Purkinje cells was confirmed by immune-electron microscopic analysis. Foxp2Ex12+ may play a role in dendritic development in Purkinje cells.
  • Daniel J Klionsky, Fabio C Abdalla, Hagai Abeliovich, Robert T Abraham, Abraham Acevedo-Arozena, Khosrow Adeli, Lotta Agholme, Maria Agnello, Patrizia Agostinis, Julio A Aguirre-Ghiso, Hyung Jun Ahn, Ouardia Ait-Mohamed, Slimane Ait-Si-Ali, Takahiko Akematsu, Shizuo Akira, Hesham M Al-Younes, Munir A Al-Zeer, Matthew L Albert, Roger L Albin, Javier Alegre-Abarrategui, Maria Francesca Aleo, Mehrdad Alirezaei, Alexandru Almasan, Maylin Almonte-Becerril, Atsuo Amano, Ravi Amaravadi, Shoba Amarnath, Amal O Amer, Nathalie Andrieu-Abadie, Vellareddy Anantharam, David K Ann, Shailendra Anoopkumar-Dukie, Hiroshi Aoki, Nadezda Apostolova, Giuseppe Arancia, John P Aris, Katsuhiko Asanuma, Nana Y O Asare, Hisashi Ashida, Valerie Askanas, David S Askew, Patrick Auberger, Misuzu Baba, Steven K Backues, Eric H Baehrecke, Ben A Bahr, Xue-Yuan Bai, Yannick Bailly, Robert Baiocchi, Giulia Baldini, Walter Balduini, Andrea Ballabio, Bruce A Bamber, Edward T W Bampton, Gábor Bánhegyi, Clinton R Bartholomew, Diane C Bassham, Robert C Bast Jr, Henri Batoko, Boon-Huat Bay, Isabelle Beau, Daniel M Béchet, Thomas J Begley, Christian Behl, Christian Behrends, Soumeya Bekri, Bryan Bellaire, Linda J Bendall, Luca Benetti, Laura Berliocchi, Henri Bernardi, Francesca Bernassola, Sébastien Besteiro, Ingrid Bhatia-Kissova, Xiaoning Bi, Martine Biard-Piechaczyk, Janice S Blum, Lawrence H Boise, Paolo Bonaldo, David L Boone, Beat C Bornhauser, Karina R Bortoluci, Ioannis Bossis, Frédéric Bost, Jean-Pierre Bourquin, Patricia Boya, Michaël Boyer-Guittaut, Peter V Bozhkov, Nathan R Brady, Claudio Brancolini, Andreas Brech, Jay E Brenman, Ana Brennand, Emery H Bresnick, Patrick Brest, Dave Bridges, Molly L Bristol, Paul S Brookes, Eric J Brown, John H Brumell, Nicola Brunetti-Pierri, Ulf T Brunk, Dennis E Bulman, Scott J Bultman, Geert Bultynck, Lena F Burbulla, Wilfried Bursch, Jonathan P Butchar, Wanda Buzgariu, Sergio P Bydlowski, Ken Cadwell, Monika Cahová, Dongsheng Cai, Jiyang Cai, Qian Cai, Bruno Calabretta, Javier Calvo-Garrido, Nadine Camougrand, Michelangelo Campanella, Jenny Campos-Salinas, Eleonora Candi, Lizhi Cao, Allan B Caplan, Simon R Carding, Sandra M Cardoso, Jennifer S Carew, Cathleen R Carlin, Virginie Carmignac, Leticia A M Carneiro, Serena Carra, Rosario A Caruso, Giorgio Casari, Caty Casas, Roberta Castino, Eduardo Cebollero, Francesco Cecconi, Jean Celli, Hassan Chaachouay, Han-Jung Chae, Chee-Yin Chai, David C Chan, Edmond Y Chan, Raymond Chuen-Chung Chang, Chi-Ming Che, Ching-Chow Chen, Guang-Chao Chen, Guo-Qiang Chen, Min Chen, Quan Chen, Steve S-L Chen, WenLi Chen, Xi Chen, Xiangmei Chen, Xiequn Chen, Ye-Guang Chen, Yingyu Chen, Yongqiang Chen, Yu-Jen Chen, Zhixiang Chen, Alan Cheng, Christopher H K Cheng, Yan Cheng, Heesun Cheong, Jae-Ho Cheong, Sara Cherry, Russ Chess-Williams, Zelda H Cheung, Eric Chevet, Hui-Ling Chiang, Roberto Chiarelli, Tomoki Chiba, Lih-Shen Chin, Shih-Hwa Chiou, Francis V Chisari, Chi Hin Cho, Dong-Hyung Cho, Augustine M K Choi, DooSeok Choi, Kyeong Sook Choi, Mary E Choi, Salem Chouaib, Divaker Choubey, Vinay Choubey, Charleen T Chu, Tsung-Hsien Chuang, Sheau-Huei Chueh, Taehoon Chun, Yong-Joon Chwae, Mee-Len Chye, Roberto Ciarcia, Maria R Ciriolo, Michael J Clague, Robert S B Clark, Peter G H Clarke, Robert Clarke, Patrice Codogno, Hilary A Coller, María I Colombo, Sergio Comincini, Maria Condello, Fabrizio Condorelli, Mark R Cookson, Graham H Coombs, Isabelle Coppens, Ramon Corbalan, Pascale Cossart, Paola Costelli, Safia Costes, Ana Coto-Montes, Eduardo Couve, Fraser P Coxon, James M Cregg, José L Crespo, Marianne J Cronjé, Ana Maria Cuervo, Joseph J Cullen, Mark J Czaja, Marcello D'Amelio, Arlette Darfeuille-Michaud, Lester M Davids, Faith E Davies, Massimo De Felici, John F de Groot, Cornelis A M de Haan, Luisa De Martino, Angelo De Milito, Vincenzo De Tata, Jayanta Debnath, Alexei Degterev, Benjamin Dehay, Lea M D Delbridge, Francesca Demarchi, Yi Zhen Deng, Jörn Dengjel, Paul Dent, Donna Denton, Vojo Deretic, Shyamal D Desai, Rodney J Devenish, Mario Di Gioacchino, Gilbert Di Paolo, Chiara Di Pietro, Guillermo Díaz-Araya, Inés Díaz-Laviada, Maria T Diaz-Meco, Javier Diaz-Nido, Ivan Dikic, Savithramma P Dinesh-Kumar, Wen-Xing Ding, Clark W Distelhorst, Abhinav Diwan, Mojgan Djavaheri-Mergny, Svetlana Dokudovskaya, Zheng Dong, Frank C Dorsey, Victor Dosenko, James J Dowling, Stephen Doxsey, Marlène Dreux, Mark E Drew, Qiuhong Duan, Michel A Duchosal, Karen Duff, Isabelle Dugail, Madeleine Durbeej, Michael Duszenko, Charles L Edelstein, Aimee L Edinger, Gustavo Egea, Ludwig Eichinger, N Tony Eissa, Suhendan Ekmekcioglu, Wafik S El-Deiry, Zvulun Elazar, Mohamed Elgendy, Lisa M Ellerby, Kai Er Eng, Anna-Mart Engelbrecht, Simone Engelender, Jekaterina Erenpreisa, Ricardo Escalante, Audrey Esclatine, Eeva-Liisa Eskelinen, Lucile Espert, Virginia Espina, Huizhou Fan, Jia Fan, Qi-Wen Fan, Zhen Fan, Shengyun Fang, Yongqi Fang, Manolis Fanto, Alessandro Fanzani, Thomas Farkas, Jean-Claude Farré, Mathias Faure, Marcus Fechheimer, Carl G Feng, Jian Feng, Qili Feng, Youji Feng, László Fésüs, Ralph Feuer, Maria E Figueiredo-Pereira, Gian Maria Fimia, Diane C Fingar, Steven Finkbeiner, Toren Finkel, Kim D Finley, Filomena Fiorito, Edward A Fisher, Paul B Fisher, Marc Flajolet, Maria L Florez-McClure, Salvatore Florio, Edward A Fon, Francesco Fornai, Franco Fortunato, Rati Fotedar, Daniel H Fowler, Howard S Fox, Rodrigo Franco, Lisa B Frankel, Marc Fransen, José M Fuentes, Juan Fueyo, Jun Fujii, Kozo Fujisaki, Eriko Fujita, Mitsunori Fukuda, Ruth H Furukawa, Matthias Gaestel, Philippe Gailly, Malgorzata Gajewska, Brigitte Galliot, Vincent Galy, Subramaniam Ganesh, Barry Ganetzky, Ian G Ganley, Fen-Biao Gao, George F Gao, Jinming Gao, Lorena Garcia, Guillermo Garcia-Manero, Mikel Garcia-Marcos, Marjan Garmyn, Andrei L Gartel, Evelina Gatti, Mathias Gautel, Thomas R Gawriluk, Matthew E Gegg, Jiefei Geng, Marc Germain, Jason E Gestwicki, David A Gewirtz, Saeid Ghavami, Pradipta Ghosh, Anna M Giammarioli, Alexandra N Giatromanolaki, Spencer B Gibson, Robert W Gilkerson, Michael L Ginger, Henry N Ginsberg, Jakub Golab, Michael S Goligorsky, Pierre Golstein, Candelaria Gomez-Manzano, Ebru Goncu, Céline Gongora, Claudio D Gonzalez, Ramon Gonzalez, Cristina González-Estévez, Rosa Ana González-Polo, Elena Gonzalez-Rey, Nikolai V Gorbunov, Sharon Gorski, Sandro Goruppi, Roberta A Gottlieb, Devrim Gozuacik, Giovanna Elvira Granato, Gary D Grant, Kim N Green, Aleš Gregorc, Frédéric Gros, Charles Grose, Thomas W Grunt, Philippe Gual, Jun-Lin Guan, Kun-Liang Guan, Sylvie M Guichard, Anna S Gukovskaya, Ilya Gukovsky, Jan Gunst, Asa B Gustafsson, Andrew J Halayko, Amber N Hale, Sandra K Halonen, Maho Hamasaki, Feng Han, Ting Han, Michael K Hancock, Malene Hansen, Hisashi Harada, Masaru Harada, Stefan E Hardt, J Wade Harper, Adrian L Harris, James Harris, Steven D Harris, Makoto Hashimoto, Jeffrey A Haspel, Shin-ichiro Hayashi, Lori A Hazelhurst, Congcong He, You-Wen He, Marie-Joseé Hébert, Kim A Heidenreich, Miep H Helfrich, Gudmundur V Helgason, Elizabeth P Henske, Brian Herman, Paul K Herman, Claudio Hetz, Sabine Hilfiker, Joseph A Hill, Lynne J Hocking, Paul Hofman, Thomas G Hofmann, Jörg Höhfeld, Tessa L Holyoake, Ming-Huang Hong, David A Hood, Gökhan S Hotamisligil, Ewout J Houwerzijl, Maria Høyer-Hansen, Bingren Hu, Chien-An A Hu, Hong-Ming Hu, Ya Hua, Canhua Huang, Ju Huang, Shengbing Huang, Wei-Pang Huang, Tobias B Huber, Won-Ki Huh, Tai-Ho Hung, Ted R Hupp, Gang Min Hur, James B Hurley, Sabah N A Hussain, Patrick J Hussey, Jung Jin Hwang, Seungmin Hwang, Atsuhiro Ichihara, Shirin Ilkhanizadeh, Ken Inoki, Takeshi Into, Valentina Iovane, Juan L Iovanna, Nancy Y Ip, Yoshitaka Isaka, Hiroyuki Ishida, Ciro Isidoro, Ken-ichi Isobe, Akiko Iwasaki, Marta Izquierdo, Yotaro Izumi, Panu M Jaakkola, Marja Jäättelä, George R Jackson, William T Jackson, Bassam Janji, Marina Jendrach, Ju-Hong Jeon, Eui-Bae Jeung, Hong Jiang, Hongchi Jiang, Jean X Jiang, Ming Jiang, Qing Jiang, Xuejun Jiang, Xuejun Jiang, Alberto Jiménez, Meiyan Jin, Shengkan Jin, Cheol O Joe, Terje Johansen, Daniel E Johnson, Gail V W Johnson, Nicola L Jones, Bertrand Joseph, Suresh K Joseph, Annie M Joubert, Gábor Juhász, Lucienne Juillerat-Jeanneret, Chang Hwa Jung, Yong-Keun Jung, Kai Kaarniranta, Allen Kaasik, Tomohiro Kabuta, Motoni Kadowaki, Katarina Kagedal, Yoshiaki Kamada, Vitaliy O Kaminskyy, Harm H Kampinga, Hiromitsu Kanamori, Chanhee Kang, Khong Bee Kang, Kwang Il Kang, Rui Kang, Yoon-A Kang, Tomotake Kanki, Thirumala-Devi Kanneganti, Haruo Kanno, Anumantha G Kanthasamy, Arthi Kanthasamy, Vassiliki Karantza, Gur P Kaushal, Susmita Kaushik, Yoshinori Kawazoe, Po-Yuan Ke, John H Kehrl, Ameeta Kelekar, Claus Kerkhoff, David H Kessel, Hany Khalil, Jan A K W Kiel, Amy A Kiger, Akio Kihara, Deok Ryong Kim, Do-Hyung Kim, Dong-Hou Kim, Eun-Kyoung Kim, Hyung-Ryong Kim, Jae-Sung Kim, Jeong Hun Kim, Jin Cheon Kim, John K Kim, Peter K Kim, Seong Who Kim, Yong-Sun Kim, Yonghyun Kim, Adi Kimchi, Alec C Kimmelman, Jason S King, Timothy J Kinsella, Vladimir Kirkin, Lorrie A Kirshenbaum, Katsuhiko Kitamoto, Kaio Kitazato, Ludger Klein, Walter T Klimecki, Jochen Klucken, Erwin Knecht, Ben C B Ko, Jan C Koch, Hiroshi Koga, Jae-Young Koh, Young Ho Koh, Masato Koike, Masaaki Komatsu, Eiki Kominami, Hee Jeong Kong, Wei-Jia Kong, Viktor I Korolchuk, Yaichiro Kotake, Michael I Koukourakis, Juan B Kouri Flores, Attila L Kovács, Claudine Kraft, Dimitri Krainc, Helmut Krämer, Carole Kretz-Remy, Anna M Krichevsky, Guido Kroemer, Rejko Krüger, Oleg Krut, Nicholas T Ktistakis, Chia-Yi Kuan, Roza Kucharczyk, Ashok Kumar, Raj Kumar, Sharad Kumar, Mondira Kundu, Hsing-Jien Kung, Tino Kurz, Ho Jeong Kwon, Albert R La Spada, Frank Lafont, Trond Lamark, Jacques Landry, Jon D Lane, Pierre Lapaquette, Jocelyn F Laporte, Lajos László, Sergio Lavandero, Josée N Lavoie, Robert Layfield, Pedro A Lazo, Weidong Le, Laurent Le Cam, Daniel J Ledbetter, Alvin J X Lee, Byung-Wan Lee, Gyun Min Lee, Jongdae Lee, Ju-Hyun Lee, Michael Lee, Myung-Shik Lee, Sug Hyung Lee, Christiaan Leeuwenburgh, Patrick Legembre, Renaud Legouis, Michael Lehmann, Huan-Yao Lei, Qun-Ying Lei, David A Leib, José Leiro, John J Lemasters, Antoinette Lemoine, Maciej S Lesniak, Dina Lev, Victor V Levenson, Beth Levine, Efrat Levy, Faqiang Li, Jun-Lin Li, Lian Li, Sheng Li, Weijie Li, Xue-Jun Li, Yan-bo Li, Yi-Ping Li, Chengyu Liang, Qiangrong Liang, Yung-Feng Liao, Pawel P Liberski, Andrew Lieberman, Hyunjung J Lim, Kah-Leong Lim, Kyu Lim, Chiou-Feng Lin, Fu-Cheng Lin, Jian Lin, Jiandie D Lin, Kui Lin, Wan-Wan Lin, Weei-Chin Lin, Yi-Ling Lin, Rafael Linden, Paul Lingor, Jennifer Lippincott-Schwartz, Michael P Lisanti, Paloma B Liton, Bo Liu, Chun-Feng Liu, Kaiyu Liu, Leyuan Liu, Qiong A Liu, Wei Liu, Young-Chau Liu, Yule Liu, Richard A Lockshin, Chun-Nam Lok, Sagar Lonial, Benjamin Loos, Gabriel Lopez-Berestein, Carlos López-Otín, Laura Lossi, Michael T Lotze, Peter Lőw, Binfeng Lu, Bingwei Lu, Bo Lu, Zhen Lu, Frédéric Luciano, Nicholas W Lukacs, Anders H Lund, Melinda A Lynch-Day, Yong Ma, Fernando Macian, Jeff P MacKeigan, Kay F Macleod, Frank Madeo, Luigi Maiuri, Maria Chiara Maiuri, Davide Malagoli, May Christine V Malicdan, Walter Malorni, Na Man, Eva-Maria Mandelkow, Stéphen Manon, Irena Manov, Kai Mao, Xiang Mao, Zixu Mao, Philippe Marambaud, Daniela Marazziti, Yves L Marcel, Katie Marchbank, Piero Marchetti, Stefan J Marciniak, Mateus Marcondes, Mohsen Mardi, Gabriella Marfe, Guillermo Mariño, Maria Markaki, Mark R Marten, Seamus J Martin, Camille Martinand-Mari, Wim Martinet, Marta Martinez-Vicente, Matilde Masini, Paola Matarrese, Saburo Matsuo, Raffaele Matteoni, Andreas Mayer, Nathalie M Mazure, David J McConkey, Melanie J McConnell, Catherine McDermott, Christine McDonald, Gerald M McInerney, Sharon L McKenna, BethAnn McLaughlin, Pamela J McLean, Christopher R McMaster, G Angus McQuibban, Alfred J Meijer, Miriam H Meisler, Alicia Meléndez, Thomas J Melia, Gerry Melino, Maria A Mena, Javier A Menendez, Rubem F S Menna-Barreto, Manoj B Menon, Fiona M Menzies, Carol A Mercer, Adalberto Merighi, Diane E Merry, Stefania Meschini, Christian G Meyer, Thomas F Meyer, Chao-Yu Miao, Jun-Ying Miao, Paul A M Michels, Carine Michiels, Dalibor Mijaljica, Ana Milojkovic, Saverio Minucci, Clelia Miracco, Cindy K Miranti, Ioannis Mitroulis, Keisuke Miyazawa, Noboru Mizushima, Baharia Mograbi, Simin Mohseni, Xavier Molero, Bertrand Mollereau, Faustino Mollinedo, Takashi Momoi, Iryna Monastyrska, Martha M Monick, Mervyn J Monteiro, Michael N Moore, Rodrigo Mora, Kevin Moreau, Paula I Moreira, Yuji Moriyasu, Jorge Moscat, Serge Mostowy, Jeremy C Mottram, Tomasz Motyl, Charbel E-H Moussa, Sylke Müller, Sylviane Muller, Karl Münger, Christian Münz, Leon O Murphy, Maureen E Murphy, Antonio Musarò, Indira Mysorekar, Eiichiro Nagata, Kazuhiro Nagata, Aimable Nahimana, Usha Nair, Toshiyuki Nakagawa, Kiichi Nakahira, Hiroyasu Nakano, Hitoshi Nakatogawa, Meera Nanjundan, Naweed I Naqvi, Derek P Narendra, Masashi Narita, Miguel Navarro, Steffan T Nawrocki, Taras Y Nazarko, Andriy Nemchenko, Mihai G Netea, Thomas P Neufeld, Paul A Ney, Ioannis P Nezis, Huu Phuc Nguyen, Daotai Nie, Ichizo Nishino, Corey Nislow, Ralph A Nixon, Takeshi Noda, Angelika A Noegel, Anna Nogalska, Satoru Noguchi, Lucia Notterpek, Ivana Novak, Tomoyoshi Nozaki, Nobuyuki Nukina, Thorsten Nürnberger, Beat Nyfeler, Keisuke Obara, Terry D Oberley, Salvatore Oddo, Michinaga Ogawa, Toya Ohashi, Koji Okamoto, Nancy L Oleinick, F Javier Oliver, Laura J Olsen, Stefan Olsson, Onya Opota, Timothy F Osborne, Gary K Ostrander, Kinya Otsu, Jing-hsiung James Ou, Mireille Ouimet, Michael Overholtzer, Bulent Ozpolat, Paolo Paganetti, Ugo Pagnini, Nicolas Pallet, Glen E Palmer, Camilla Palumbo, Tianhong Pan, Theocharis Panaretakis, Udai Bhan Pandey, Zuzana Papackova, Issidora Papassideri, Irmgard Paris, Junsoo Park, Ohkmae K Park, Jan B Parys, Katherine R Parzych, Susann Patschan, Cam Patterson, Sophie Pattingre, John M Pawelek, Jianxin Peng, David H Perlmutter, Ida Perrotta, George Perry, Shazib Pervaiz, Matthias Peter, Godefridus J Peters, Morten Petersen, Goran Petrovski, James M Phang, Mauro Piacentini, Philippe Pierre, Valérie Pierrefite-Carle, Gérard Pierron, Ronit Pinkas-Kramarski, Antonio Piras, Natik Piri, Leonidas C Platanias, Stefanie Pöggeler, Marc Poirot, Angelo Poletti, Christian Poüs, Mercedes Pozuelo-Rubio, Mette Prætorius-Ibba, Anil Prasad, Mark Prescott, Muriel Priault, Nathalie Produit-Zengaffinen, Ann Progulske-Fox, Tassula Proikas-Cezanne, Serge Przedborski, Karin Przyklenk, Rosa Puertollano, Julien Puyal, Shu-Bing Qian, Liang Qin, Zheng-Hong Qin, Susan E Quaggin, Nina Raben, Hannah Rabinowich, Simon W Rabkin, Irfan Rahman, Abdelhaq Rami, Georg Ramm, Glenn Randall, Felix Randow, V Ashutosh Rao, Jeffrey C Rathmell, Brinda Ravikumar, Swapan K Ray, Bruce H Reed, John C Reed, Fulvio Reggiori, Anne Régnier-Vigouroux, Andreas S Reichert, John J Reiners Jr, Russel J Reiter, Jun Ren, José L Revuelta, Christopher J Rhodes, Konstantinos Ritis, Elizete Rizzo, Jeffrey Robbins, Michel Roberge, Hernan Roca, Maria C Roccheri, Stephane Rocchi, H Peter Rodemann, Santiago Rodríguez de Córdoba, Bärbel Rohrer, Igor B Roninson, Kirill Rosen, Magdalena M Rost-Roszkowska, Mustapha Rouis, Kasper M A Rouschop, Francesca Rovetta, Brian P Rubin, David C Rubinsztein, Klaus Ruckdeschel, Edmund B Rucker 3rd, Assaf Rudich, Emil Rudolf, Nelson Ruiz-Opazo, Rossella Russo, Tor Erik Rusten, Kevin M Ryan, Stefan W Ryter, David M Sabatini, Junichi Sadoshima, Tapas Saha, Tatsuya Saitoh, Hiroshi Sakagami, Yasuyoshi Sakai, Ghasem Hoseini Salekdeh, Paolo Salomoni, Paul M Salvaterra, Guy Salvesen, Rosa Salvioli, Anthony M J Sanchez, José A Sánchez-Alcázar, Ricardo Sánchez-Prieto, Marco Sandri, Uma Sankar, Poonam Sansanwal, Laura Santambrogio, Shweta Saran, Sovan Sarkar, Minnie Sarwal, Chihiro Sasakawa, Ausra Sasnauskiene, Miklós Sass, Ken Sato, Miyuki Sato, Anthony H V Schapira, Michael Scharl, Hermann M Schätzl, Wiep Scheper, Stefano Schiaffino, Claudio Schneider, Marion E Schneider, Regine Schneider-Stock, Patricia V Schoenlein, Daniel F Schorderet, Christoph Schüller, Gary K Schwartz, Luca Scorrano, Linda Sealy, Per O Seglen, Juan Segura-Aguilar, Iban Seiliez, Oleksandr Seleverstov, Christian Sell, Jong Bok Seo, Duska Separovic, Vijayasaradhi Setaluri, Takao Setoguchi, Carmine Settembre, John J Shacka, Mala Shanmugam, Irving M Shapiro, Eitan Shaulian, Reuben J Shaw, James H Shelhamer, Han-Ming Shen, Wei-Chiang Shen, Zu-Hang Sheng, Yang Shi, Kenichi Shibuya, Yoshihiro Shidoji, Jeng-Jer Shieh, Chwen-Ming Shih, Yohta Shimada, Shigeomi Shimizu, Takahiro Shintani, Orian S Shirihai, Gordon C Shore, Andriy A Sibirny, Stan B Sidhu, Beata Sikorska, Elaine C M Silva-Zacarin, Alison Simmons, Anna Katharina Simon, Hans-Uwe Simon, Cristiano Simone, Anne Simonsen, David A Sinclair, Rajat Singh, Debasish Sinha, Frank A Sinicrope, Agnieszka Sirko, Parco M Siu, Efthimios Sivridis, Vojtech Skop, Vladimir P Skulachev, Ruth S Slack, Soraya S Smaili, Duncan R Smith, Maria S Soengas, Thierry Soldati, Xueqin Song, Anil K Sood, Tuck Wah Soong, Federica Sotgia, Stephen A Spector, Claudia D Spies, Wolfdieter Springer, Srinivasa M Srinivasula, Leonidas Stefanis, Joan S Steffan, Ruediger Stendel, Harald Stenmark, Anastasis Stephanou, Stephan T Stern, Cinthya Sternberg, Björn Stork, Peter Strålfors, Carlos S Subauste, Xinbing Sui, David Sulzer, Jiaren Sun, Shi-Yong Sun, Zhi-Jun Sun, Joseph J Y Sung, Kuninori Suzuki, Toshihiko Suzuki, Michele S Swanson, Charles Swanton, Sean T Sweeney, Lai-King Sy, Gyorgy Szabadkai, Ira Tabas, Heinrich Taegtmeyer, Marco Tafani, Krisztina Takács-Vellai, Yoshitaka Takano, Kaoru Takegawa, Genzou Takemura, Fumihiko Takeshita, Nicholas J Talbot, Kevin S W Tan, Keiji Tanaka, Kozo Tanaka, Daolin Tang, Dingzhong Tang, Isei Tanida, Bakhos A Tannous, Nektarios Tavernarakis, Graham S Taylor, Gregory A Taylor, J Paul Taylor, Lance S Terada, Alexei Terman, Gianluca Tettamanti, Karin Thevissen, Craig B Thompson, Andrew Thorburn, Michael Thumm, FengFeng Tian, Yuan Tian, Glauco Tocchini-Valentini, Aviva M Tolkovsky, Yasuhiko Tomino, Lars Tönges, Sharon A Tooze, Cathy Tournier, John Tower, Roberto Towns, Vladimir Trajkovic, Leonardo H Travassos, Ting-Fen Tsai, Mario P Tschan, Takeshi Tsubata, Allan Tsung, Boris Turk, Lorianne S Turner, Suresh C Tyagi, Yasuo Uchiyama, Takashi Ueno, Midori Umekawa, Rika Umemiya-Shirafuji, Vivek K Unni, Maria I Vaccaro, Enza Maria Valente, Greet Van den Berghe, Ida J van der Klei, Wouter van Doorn, Linda F van Dyk, Marjolein van Egmond, Leo A van Grunsven, Peter Vandenabeele, Wim P Vandenberghe, Ilse Vanhorebeek, Eva C Vaquero, Guillermo Velasco, Tibor Vellai, Jose Miguel Vicencio, Richard D Vierstra, Miquel Vila, Cécile Vindis, Giampietro Viola, Maria Teresa Viscomi, Olga V Voitsekhovskaja, Clarissa von Haefen, Marcela Votruba, Keiji Wada, Richard Wade-Martins, Cheryl L Walker, Craig M Walsh, Jochen Walter, Xiang-Bo Wan, Aimin Wang, Chenguang Wang, Dawei Wang, Fan Wang, Fen Wang, Guanghui Wang, Haichao Wang, Hong-Gang Wang, Horng-Dar Wang, Jin Wang, Ke Wang, Mei Wang, Richard C Wang, Xinglong Wang, Xuejun Wang, Ying-Jan Wang, Yipeng Wang, Zhen Wang, Zhigang Charles Wang, Zhinong Wang, Derick G Wansink, Diane M Ward, Hirotaka Watada, Sarah L Waters, Paul Webster, Lixin Wei, Conrad C Weihl, William A Weiss, Scott M Welford, Long-Ping Wen, Caroline A Whitehouse, J Lindsay Whitton, Alexander J Whitworth, Tom Wileman, John W Wiley, Simon Wilkinson, Dieter Willbold, Roger L Williams, Peter R Williamson, Bradly G Wouters, Chenghan Wu, Dao-Cheng Wu, William K K Wu, Andreas Wyttenbach, Ramnik J Xavier, Zhijun Xi, Pu Xia, Gengfu Xiao, Zhiping Xie, Zhonglin Xie, Da-zhi Xu, Jianzhen Xu, Liang Xu, Xiaolei Xu, Ai Yamamoto, Akitsugu Yamamoto, Shunhei Yamashina, Michiaki Yamashita, Xianghua Yan, Mitsuhiro Yanagida, Dun-Sheng Yang, Elizabeth Yang, Jin-Ming Yang, Shi Yu Yang, Wannian Yang, Wei Yuan Yang, Zhifen Yang, Meng-Chao Yao, Tso-Pang Yao, Behzad Yeganeh, Wei-Lien Yen, Jia-jing Yin, Xiao-Ming Yin, Ook-Joon Yoo, Gyesoon Yoon, Seung-Yong Yoon, Tomohiro Yorimitsu, Yuko Yoshikawa, Tamotsu Yoshimori, Kohki Yoshimoto, Ho Jin You, Richard J Youle, Anas Younes, Li Yu, Long Yu, Seong-Woon Yu, Wai Haung Yu, Zhi-Min Yuan, Zhenyu Yue, Cheol-Heui Yun, Michisuke Yuzaki, Olga Zabirnyk, Elaine Silva-Zacarin, David Zacks, Eldad Zacksenhaus, Nadia Zaffaroni, Zahra Zakeri, Herbert J Zeh 3rd, Scott O Zeitlin, Hong Zhang, Hui-Ling Zhang, Jianhua Zhang, Jing-Pu Zhang, Lin Zhang, Long Zhang, Ming-Yong Zhang, Xu Dong Zhang, Mantong Zhao, Yi-Fang Zhao, Ying Zhao, Zhizhuang J Zhao, Xiaoxiang Zheng, Boris Zhivotovsky, Qing Zhong, Cong-Zhao Zhou, Changlian Zhu, Wei-Guo Zhu, Xiao-Feng Zhu, Xiongwei Zhu, Yuangang Zhu, Teresa Zoladek, Wei-Xing Zong, Antonio Zorzano, Jürgen Zschocke, Brian Zuckerbraun
    Autophagy 8 (4) 445 - 544 1554-8627 2012/04 [Refereed][Not invited]
     
    In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
  • Eriko Fujita, Yuko Tanabe, Mariko Y. Momoi, Takashi Momoi
    NEUROSCIENCE LETTERS 506 (2) 277 - 280 0304-3940 2012/01 [Refereed][Not invited]
     
    Foxp2(R552H) knock-in (KI) mice carrying a mutation related to human speech-language disorder exhibit impaired ultrasonic vocalization and poor Purkinje cell development. Foxp2 is a forkhead domain-containing transcriptional repressor that associates with its co-repressor CtBP; Foxp2(R552H) displays reduced DNA binding activity. A genetic connection between FOXP2 and CNTNAP2 has been demonstrated in vitro, but not in vivo. Here we show that Cntnap2 mRNA levels significantly increased in the cerebellum of Foxp2(R552H) KI pups, although the cerebellar population of Foxp2-positive Purkinje cells was very small. Furthermore, Cntnap2 immunofluorescence did not decrease in the poorly developed Purkinje cells of Foxp2(R552H) KI pups, although synaptophysin immunofluorescence decreased. Cntnap2 and CtBP were ubiquitously expressed, while Foxp2 co-localized with CtBP only in Purkinje cells. Taken together, these observations suggest that Foxp2 may regulate ultrasonic vocalization by associating with CtBP in Purkinje cells; Cntnap2 may be a target of this co-repressor. (C) 2011 Elsevier Ireland Ltd. All rights reserved.
  • Eriko Fujita, Yuko Tanabe, Beat A. Imhof, Mariko Y. Momoi, Takashi Momoi
    PLOS ONE 7 (1) e30151  1932-6203 2012/01 [Refereed][Not invited]
     
    Foxp2(R552H) knock-in (KI) mouse pups with a mutation related to human speech-language disorders exhibit poor development of cerebellar Purkinje cells and impaired ultrasonic vocalization (USV), a communication tool for mother-offspring interactions. Thus, human speech and mouse USV appear to have a Foxp2-mediated common molecular basis in the cerebellum. Mutations in the gene encoding the synaptic adhesion molecule CADM1 (RA175/Necl2/SynCAM1/Cadm1) have been identified in people with autism spectrum disorder (ASD) who have impaired speech and language. In the present study, we show that both Cadm1-deficient knockout (KO) pups and Foxp2(R552H) KI pups exhibit impaired USV and smaller cerebellums. Cadm1 was preferentially localized to the apical-distal portion of the dendritic arbor of Purkinje cells in the molecular layer of wild-type pups, and VGluT1 level decreased in the cerebellum of Cadm1 KO mice. In addition, we detected reduced immunoreactivity of Cadm1 and VGluT1 on the poorly developed dendritic arbor of Purkinje cells in the Foxp2(R552H) KI pups. However, Cadm1 mRNA expression was not altered in the Foxp2(R552H) KI pups. These results suggest that although the Foxp2 transcription factor does not target Cadm1, Cadm1 at the synapses of Purkinje cells and parallel fibers is necessary for USV function. The loss of Cadm1-expressing synapses on the dendrites of Purkinje cells may be associated with the USV impairment that Cadm1 KO and Foxp2(R552H) KI mice exhibit.
  • Koji Shimoke, Yoshinori Matsuki, Kenji Fukunaga, Yoshinobu Matsumura, Eriko Fujita, Kensuke Sugihara, Masamichi Nobuhara, Hiroki Maruoka, Toshihiko Ikeuchi, Motoshige Kudo
    CELLULAR AND MOLECULAR NEUROBIOLOGY 31 (5) 795 - 802 0272-4340 2011/07 [Refereed][Not invited]
     
    Following endoplasmic reticulum (ER) stress, cerebral infarctions have been reported to involve an apoptotic process, including the activation of the caspase cascade. To confirm whether fragmented caspase-12, which is activated by cleavage and is detectable during ER stress, is also involved in embolic cerebral infarctions in rats, we adopted an autologous blood clot model for the analysis of cerebral infarctions. We performed experiments in rats with brain infarctions, which are closely related to embolic cerebral infarctions. We utilized a homologous blood clot, i.e., natural materials, to form the infarct area. Our findings reveal that caspase-12 is fragmented when infarct areas form in cerebral cortical neurons. Interestingly, we observed that these fragments translocated to the nuclei of not only cerebral cortical neurons but hippocampal neurons. We further found that glucose-regulated protein 78 (GRP78), a marker of ER stress, is up-regulated in both cerebral cortical and hippocampal neurons during cerebral infarction. This result suggests that the fragmentation of caspase-12 and the subsequent nuclear translocation of these fragments are involved in the brain infarction process in rats.
  • Yuko Tanabe, Eriko Fujita, Takashi Momoi
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 410 (3) 593 - 596 0006-291X 2011/07 [Refereed][Not invited]
     
    FOXP2 is a forkhead box-containing transcription factor with several recognizable sequence motifs. However, little is known about the FOXP2-associated proteins except for C-terminal binding protein (CtBP). In the present study, we attempted to isolate the FOXP2-associated protein with a yeast two-hybrid system using the C-terminal region, including the forkhead domain, as a bait probe, and identified protection of telomeres 1 (POT1) as a FOXP2-associated protein. Immunoprecipitation assay confirmed the association with FOXP2 and POT1. POT1 alone localized in the cytoplasm but co-localized with FOXP2 and the forkhead domain of FOXP2 in nuclei. However, both FOXP2 with mutated nuclear localization signals and (R553H) mutated forkhead, which is associated with speech-language disorder, prevented the nuclear translocation of POT1. These results suggest that FOXP2 is a binding partner for the nuclear translocation of POT1. As loss of POT1 function induces the cell arrest, the impaired nuclear translocation of POT1 in the developing neuronal cells may be associated with the pathogenesis of speech-language disorder with FOXP2(R553H) mutation. (C) 2011 Elsevier Inc. All rights reserved.
  • Yuki Takayanagi, Eriko Fujita, Zhiling Yu, Takanori Yamagata, Mariko Y. Momoi, Takashi Momoi, Tatsushi Onaka
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 396 (3) 703 - 708 0006-291X 2010/06 [Refereed][Not invited]
     
    Cell adhesion molecule 1 (CADM1), a member of the immunoglobulin superfamily, mediates synaptic cell adhesion. Missense mutations in the CADM1 gene have been identified in autism spectrum disorder (ASD) patients. In the present study, we examined emotional behaviors, social behaviors and motor performances in Cadm1-knockout (KO) mice. Cadm1-KO mice showed increased anxiety-related behavior in open-field and light-dark transition tests. Social behaviors of Cadm1-KO mice were impaired in social interaction, resident-intruder and social memory/recognition tests. Furthermore, motor coordination and gait of Cadm1-MO mice were impaired in rotarod and footprint tests. Our study demonstrates that CADM1 plays roles in regulating emotional behaviors, social behaviors and motor performances, and that CADM1 has important implications for psychiatric disorders with disruptions in social behavior, such as autism. (C) 2010 Elsevier Inc. All rights reserved.
  • Toshihiko Hibino, Eriko Fujita, Yumiko Tsuji, Jotaro Nakanishi, Haruhi Iwaki, Chika Katagiri, Takashi Momoi
    JOURNAL OF CELLULAR BIOCHEMISTRY 109 (3) 487 - 497 0730-2312 2010/02 [Refereed][Not invited]
     
    Restricted expression of caspase-14 in differentiating keratinocytes suggests the involvement of caspase-14 in terminal differentiation. We purified active caspase-14 from human cornified cells with sequential chromatographic procedures. Specific activity increased 764-fold with a yield of 9.1%. Purified caspase-14 revealed the highest activity on WEHD-methylcoumaryl-amide (MCA), although YVAD-MCA, another caspase-1 substrate, was poorly hydrolyzed. The purified protein was a heterodimer with 17 and 11 kDa subunits. N-terminal and C-terminal analyses demonstrated that the large subunit consisted of Ser(6)-Asp(146) and N-terminal of small Subunit was identified as Lys(153). We successfully developed an antiserum (anti-h14D146) directed against the Asp(146) cleavage site, which reacted only with active caspase-14 but not with procaspase-14. Furthermore we confirmed that anti-h14D146 did not show any reactivity to the active forms of other caspases. Immunohistochemical analysis demonstrated that anti-h14D146 staining was mostly restricted to the cornified layer and co-localized with some of the TUNEL positive-granular cells in the normal human epidermis. UV radiation study demonstrated that caspase-3 was activated and co-localized with TUNEL-positive cells in the middle layer of human epidermis. In contrast, we could not detect caspase-14 activation in response to UV. Our study revealed tightly regulated action of caspase-14, in which only the terminal differentiation of keratinocytes controls its activation process. J. Cell. Biochem. 109: 487-497, 2010. (C) 2009 Wiley-Liss, Inc.
  • Takashi Momoi, Eriko Fujita, Haruki Senoo, Mariko Momoi
    CELL BIOLOGY INTERNATIONAL 34 (1) 13 - 19 1065-6995 2010/01 [Refereed][Not invited]
     
    The molecular pathogenesis of ASD (autism spectrum disorder), one of the heritable neurodevelopmental disorders, is not well understood, although over 15 autistic-susceptible gene loci have been extensively studied. A major issue is whether the proteins that these candidate genes encode are involved in general function and signal transduction. Several mutations in genes encoding synaptic adhesion molecules such as neuroligin, neurexin, CNTNAP (contactin-associated protein) and CADM1 (cell-adhesion molecule 1) found in ASD suggest that impaired synaptic function is the underlying pathogenesis. However, knockout mouse models of these mutations do not show all of the autism-related symptoms, suggesting that gain-of-function in addition to loss-of-function arising from these mutations may be associated with ASD pathogenesis. Another finding is that family members with a given mutation frequently do not manifest autistic symptoms, which possibly may be because of gender effects, dominance theory and environmental factors, including hormones and stress. Thus epigenetic factors complicate our understanding of the relationship between these mutated genes and ASD pathogenesis. We focus in the present review on findings that ER (endoplasmic reticulum) stress arising from these mutations causes a trafficking disorder of synaptic receptors, such as GABA (gamma-aminobutyric acid) B-receptors, and leads to their impaired synaptic function and signal transduction. In the present review we propose a hypothesis that ASD pathogenesis is linked not only to loss-of-function but also to gain-of-function, with an ER stress response to unfolded proteins under the influence of epigenetic factors.
  • Yu Zhiling, Eriko Fujita, Yuko Tanabe, Takanori Yamagata, Takashi Momoi, Mariko Y. Momoi
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 377 (3) 926 - 929 0006-291X 2008/12 [Refereed][Not invited]
     
    The unified idea on the molecular pathogenesis of Autism Spectrum Disorder (ASD) is still unknown although mutations in genes encoding neuroligins and SHANK3 have been shown in a small part of the patients. RA175/SynCAM1/CADM1(CADM1), a member of immunoglobilin superfamily, is another synaptic cell adhesion molecule. To clarify the idea that impaired synaptogenesis underlies the pathogenesis of ASD, we examined the relationship between mutations in the CADM1 gene and ASD. We found two missense Mutations, C739A(H246N) and A755C(Y251S), in the CADM1 gene of male Caucasian ASD patients and their family members. Both mutations were located in the third immunoglobulin domain, which is essential for trans-active interaction. The mutated CADM1 exhibited less amount of high molecular weight with the Matured oligosaccharide, defective trafficking to the cell surface, and more susceptibility to the cleavage and or degradation. Our findings provide key support for the unified idea that impaired synaptogenesis underlies the pathogenesis of ASD. (C) 2008 Published by Elsevier Inc.
  • Yuko Tanabe, Tadashi Kasahara, Takashi Momoi, Eriko Fujita
    NEUROSCIENCE LETTERS 444 (1) 16 - 21 0304-3940 2008/10 [Refereed][Not invited]
     
    RA175/SynCAM1, a member of immunoglobulin superfamily 4 (Igsf4; recently named Cadm1), is a cell adhesion molecule involved in the formation of a functional synapse. Little is known about the modulation of RA175/SynCAM1-mediated synaptic formation and plasticity. Neurons express two major isoforms containing exons 7-8a-8b-9 and exons 7-8b-9. We found that these isoforms were processed within an 11-amino acid sequence, encoded by exon 8b, near the transmembrane domain. TNF-alpha protease inhibitor- 1 (TAPI-1) blocked the processing of RA175/SynCAM1 (exons 7-8a-8b-9). Furthermore, TAPI-1 increased the number of synaptophysin and RA175/SynCAM1 colocalization on the dendrites of neurons. Noncleaved RA175/SynCAM1 was located at the synapse and membrane-bound, cleaved fragments were detected at the non-synaptic region of dendrites. These results suggest that tumor necrosis factor-alpha-converting enzyme (TACE)/ADAM17-like proteases play a role in synaptic formation to generate specific neuronal connections by processing the excess amount of RA175/SynCAM1 located in the non-synaptic region. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
  • Eriko Fujita, Yuko Tanabe, Akira Shiota, Masatsugu Ueda, Kiyotaka Suwa, Mariko Y. Momoi, Takashi Momoi
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 105 (8) 3117 - 3122 0027-8424 2008/02 [Refereed][Not invited]
     
    Previous studies have demonstrated that mutation in the forkhead domain of the forkhead box P2 (FOXP2) protein (R553H) causes speech-language disorders. To further analyze FOXP2 function in speech learning, we generated a knockin (KI) mouse for Foxp2 (R552H) [Foxp2 (R552H)-KI], corresponding to the human FOXP2 (R553H) mutation, by homologous recombination. Homozygous Foxp2 (R552H)-KI mice showed reduced weight, immature development of the cerebellum with incompletely folded folia, Purkinje cells with poor dendritic arbors and less synaptophysin immunoreactivity, and achieved crisis stage for survival 3 weeks after birth. At postnatal day 10, these mice also showed severe ultrasonic vocalization (USV) and motor impairment, whereas the heterozygous Foxp2 (R552H)-KI mice exhibited modest impairments. Similar to the wild-type protein, Foxp2 (R552H) localized in the nuclei of the Purkinje cells and the thalamus, striatum, cortex, and hippocampus (CA1) neurons of the homozygous Foxp2 (R552H)-KI mice (postnatal day 10), and some of the neurons showed nuclear aggregates of Foxp2 (R552H). In addition to the immature development of the cerebellum, Foxp2 (R552H) nuclear aggregates may further compromise the function of the Purkinje cells and cerebral neurons of the homozygous mice, resulting in their death. In contrast, heterozygous Foxp2 (R552H)-KI mice, which showed modest impairment of USVs with different USV qualities and which did not exhibit nuclear aggregates, should provide insights into the common molecular mechanisms between the mouse USV and human speech learning and the relationship between the USV and motor neural systems.
  • Fusako Usuki, Eriko Fujita, Noboru Sasagawa
    NEUROTOXICOLOGY 29 (1) 22 - 30 0161-813X 2008/01 [Refereed][Not invited]
     
    Cellular stress responses following exposure to methylmercury (MeHg) were investigated using myogenic cell lines that showed different susceptibilities to MeHg. The susceptible cell line showed apoptosis within 24 h after exposure to low levels of MeHg. The activation of caspase 12, 9, and 3 was detected in the apoptotic cells at 14-16 h after MeHg exposure, suggesting that MeHg causes apoptosis via both mitochondria- and endoplasmic reticulum (ER)-generated processes. An early increase in the level of intracellular reactive oxygen species (ROS) was quantitatively recognized since 2-3 h after exposure to MeHg in both MeHg-susceptible and non-susceptible cell lines; however, the increase was lower in the latter cell line. The phosphorylation of apoptosis signal-regulating kinase 1 (ASK1) was also recognized in both cell lines, with the increase in intracellular ROS. However, the activation of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) pathways was observed only in the MeHg-susceptible cell line. In contrast, the non-susceptible cell line exhibited activation of the cell survival ERK pathway. Up-regulation of metallothioneine I and Hic-5 mRNAs encoding proteins induced by oxidative stress was recognized during the early stage of MeHg cytotoxicity in the MeHg-susceptible cell line. Quantitative real-time PCR and western blot analyses confirmed that ER stress is a late event during MeHg cytotoxicity. Coaddition of the antioxidant Trolox dramatically suppressed the increase in the level of ROS, activation of caspases and, finally, apoptosis. However, later treatment with Trolox attenuated its protective effect against MeHg cytotoxicity. The results indicate that failure to protect cells against the early oxidative stress triggers ER stress and apoptosis processes. Combined treatment with protective factors against oxidative and ER stresses is necessary, especially in the later stages of MeHg cytotoxicity. (c) 2007 Elsevier Inc. All rights reserved.
  • Eriko Fujita, Yuko Tanabe, Tomonori Hirose, Michel Aurrand-Lions, Tadashi Kasahara, Beat A. Imhof, Shigeo Ohno, Takashi Momoi
    AMERICAN JOURNAL OF PATHOLOGY 171 (6) 1800 - 1810 0002-9440 2007/12 [Refereed][Not invited]
     
    IGSF4a/RA175/SynCAM (RA175) and junctional adhesion molecules (Jams) are members of the immunoglobulin superfamily with a PDZ-binding domain at their C termini. Deficiency of Ra175 (Ra175(-/-)) as well as jam-C deficiency (Jam-C-/-) causes the defect of the spermatid differentiation, oligo-astheno-teratozoospermia. Ra175(-/-) elongating spermatids; fail to mature further, whereas Jam-C-/- round spermatids lose cell polarity, and most of Jam-C-/- elongated spermatids are completely lost. RA175 and Jam-C seem to have similar but distinct functional roles during spermatid. differentiation. Here we show that the cell polarity protein Par-3 with PDZ domains, a binding partner of jams, is one of the associated proteins of the cytoplasmic region of RA175 in testis. Par-3 and Jam-C are partly co-localized with RA175 in the elongating and elongated spermatids; their distributions overlapped with that of RA175 on the tips of the dorsal region of the head of the elongating spermatid (steps 9 to 12) in the wild type. In the Ra175(-/-)-elongating spermatid, Par-3 was absent, and Jam-C was absent or abnormally localized. The RA175 formed a ternary complex with Jam-C via interaction with Par-3. The lack of the ternary complex in the Ra175(-/-) elongating spermatid may cause the defect of the specialized adhesion structures, resulting in the oligo-astheno-teratozoospermia.
  • Naohiro Uchio, Yoko Oma, Kazuya Toriumi, Noboru Sasagawa, Isei Tanida, Eriko Fujita, Yoriko Kouroku, Reiko Kuroda, Takashi Momoi, Shoichi Ishiura
    FEBS JOURNAL 274 (21) 5619 - 5627 1742-464X 2007/11 [Refereed][Not invited]
     
    Many human proteins have homopolymeric amino acid (HPAA) tracts, but their physiological functions or cellular effects are not well understood. Previously, we expressed 20 HPAAs in mammalian cells and showed characteristic intracellular localization, in that hydrophobic HPAAs aggregated strongly and caused high cytotoxicity in proportion to their hydrophobicity. In the present study, we investigated the cytotoxicity of these aggregate-prone hydrophobic HPAAs, assuming that the ubiquitin proteasome system is impaired in the same manner as other well-known aggregate-prone polyglutamine-containing proteins. Some highly hydrophobic HPAAs caused a deficiency in the ubiquitin proteasome system and excess endoplasmic reticulum stress, leading to apoptosis. These results indicate that the property of causing excess endoplasmic reticulum stress by proteasome impairment may contribute to the strong cytotoxicity of highly hydrophobic HPAAs, and proteasome impairment and the resulting excess endoplasmic reticulum stress is not a common cytotoxic effect of aggregate-prone proteins such as polyglutamine.
  • Eriko Fujita, Yoriko Kouroku, Atsushi Isoai, Hiromichi Kumagai, Akifumi Misutani, Chie Matsuda, Yukiko K. Hayashi, Takashi Momoi
    HUMAN MOLECULAR GENETICS 16 (6) 618 - 629 0964-6906 2007/03 [Refereed][Not invited]
     
    Dysferlin is a type-II transmembrane protein and the causative gene of limb girdle muscular dystrophy type 2B and Miyoshi myopathy (LGMD2B/MM), in which specific loss of dysferlin labeling has been frequently observed. Recently, a novel mutant (L1341P) dysferlin has been shown to aggregate in the muscle of the patient. Little is known about the relationship between degradation of dysferlin and pathogenesis of LGMD2B/MM. Here, we examined the degradation of normal and mutant (L1341P) dysferlin. Wild-type (wt) dysferlin mainly localized to the ER/Golgi, associated with retrotranslocon, Sec61 alpha, and VCP(p97), and was degraded by endoplasmic reticulum (ER)-associated degradation system (ERAD) composed of ubiquitin/proteasome. In contrast, mutant dysferlin spontaneously aggregated in the ER and induced eukaryotic translation initiation factor 2 alpha (eIF2 alpha) phosphorylation and LC3 conversion, a key step for autophagosome formation, and finally, ER stress cell death. Unlike proteasome inhibitor, E64d/pepstatin A, inhibitors of lysosomal proteases did not stimulate the accumulation of the wt-dysferlin, but stimulated aggregation of mutant dysferlin in the ER. Furthermore, deficiency of Atg5 and dephosphorylation of eIF2 alpha, key molecules for LC3 conversion, also stimulated the mutant dysferlin aggregation in the ER. Rapamycin, which induces eIF2 alpha phosphorylation-mediated LC3 conversion, inhibited mutant dysferlin aggregation in the ER. Thus, mutant dysferlin aggregates in the ER-stimulated autophagosome formation to engulf them via activation of ER stress-eIF2 alpha phosphorylation pathway. We propose two ERAD models for dysferlin degradation, ubiquitin/proteasome ERAD(I) and autophagy/lysosome ERAD(II). Mutant dysferlin aggregates on the ER are degraded by the autophagy/lysosome ERAD(II), as an alternative to ERAD(I), when retrotranslocon/ERAD(I) system is impaired by these mutant aggregates.
  • Akifumi Mizutani, Ayumi Matsuzaki, Mariko Y. Momoi, Eriko Fujita, Yuko Tanabe, Takashi Momoi
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 353 (4) 869 - 874 0006-291X 2007/02 [Refereed][Not invited]
     
    Although a mutation (R553H) in the forkhead box (FOX)P2 gene is associated with speech/language disorder, little is known about the function of FOXP2 or its relevance to this disorder. In the present study, we identify the forkhead nuclear localization domains that contribute to the cellular distribution of FOXP2. Nuclear localization of FOXP2 depended on two distally separated nuclear localization signals in the forkhead domain. A truncated version of FOXP2 lacking the leu-zip, Zn2+ finger, and forkhead domains that was observed in another patient with speech abnormalities demonstrated an aggregated cytoplasmic localization. Furthermore, FOXP2 (R553H) mainly exhibited a cytoplasmic localization despite retaining interactions with nuclear transport proteins (importin a and P). Interestingly, wild type FOXP2 promoted the transport of FOXP2 (R553H) into the nucleus. Mutant and wild type FOXP2 heterodimers in the nucleus or FOXP2 R553H in the cytoplasm may underlie the pathogenesis of the autosomal dominant speech/language disorder. (c) 2006 Elsevier Inc. All rights reserved.
  • E Fujita, Y Kouroku, S Ozeki, Y Tanabe, Y Toyama, M Maekawa, N Kojima, H Senoo, K Toshimori, T Momoi
    MOLECULAR AND CELLULAR BIOLOGY 26 (2) 718 - 726 0270-7306 2006/01 [Refereed][Not invited]
     
    RA175/TSLC1/SynCAM/IGSF4A (RA175), a member of the immunoglobulin superfamilly with Ca(2+)-independent homophilic trans-cell adhesion activity, participates in synaptic and epithelial cell junctions. To clarify the biological function of RA175, we disrupted the mouse Igsf4a (Ra175/Tslc1/SynCam/Igsf4a Ra175) gene. Male mice lacking both alleles of Ra175 (Ra175(-/-)) were infertile and showed oligo-astheno-teratozoospermia; almost no mature motile spermatozoa were found in the epididymis. Heterozygous males and females and homozygous null females were fertile and had no overt developmental defects. RA175 was mainly expressed on the cell junction of spermatocytes, elongating and elongated spermatids (steps 9 to 15) in wild-type testes; the RA175 expression was restricted to the distal site (tail side) but not to the proximal site (head side) in elongated spermatids. In Ra175(-/-) testes, elongated and mature spermatids (steps 13 to 16) were almost undetectable; round spermatids were morphologically normal, but elongating spermatids (steps 9 to 12) failed to mature further and to translocate to the adluminal surface. The remaining elongating spermatids at improper positions were finally phagocytosed by Sertoli cells. Furthermore, undifferentiated and abnormal spermatids exfoliated into the tubular lumen from adluminall surfaces. Thus, RA175-based cell junction is necessary for retaining elongating spermatids in the invagination of Sertoli cells for their maturation and translocation to the adluminall surface for timely release.
  • E Fujita, K Urase, A Soyama, Y Kouroku, T Momoi
    DEVELOPMENTAL BRAIN RESEARCH 154 (2) 199 - 209 0165-3806 2005/02 [Refereed][Not invited]
     
    RA175 is a new member of the immunoglobulin superfamily with trans interaction activity, and it plays a role as a tumor suppressor in lung carcinoma (TSLC1) and as a cell adhesion molecule promoting the formation of functional synapses (SynCAM). Little is known about the biological function of R-A175/TSLC1/SynCAM neural network formation during neurogenesis. We examined the distribution and colocalization of the RA175/TSLC1/SynCAM protein with other members of the immunoglobulin superfamily such as NCAM, L1, and TAG-1 in the mouse developing nervous system. Consistent with the expression of RA175/TSLC1/SynCAM mRNA, the protein was localized in the brain neuroepithelium at embryonic day (E) 9.5, neural crest at E10.5, motor neurons at E10.5, and olfactory epithelium at E16.5. In contrast with its mRNA, the protein was intensely detected on the fasciculated axons in the floor plates, ventral root, and dorsal funiculus in the E10.5-11.5 spinal cord and colocalized with NCAM and L1 on the ventral root and dorsal funiculus and partly colocalized with TAG-I on the commissural axons and dorsal faniculus. In the E13.5-15.5 brain, RA175/TSLC1/SynCAM colocalized with NCAM and L1 on the developing thalamocortical fibers from the internal capsule (IC) and partly colocalized with TAG-1 on the cortical efferent axons in the intermediate zone (IZ). RA175/TSLC1/SynCAM was localized on the axons of some of the cortical neurons cultured in vitro. Thus, in addition to cell adhesion activity in the neuroepithelium and the synapses, RA175/TSLC1/SynCAM may be involved in neuronal migration, axon growth, pathfinding, and fasciculation on the axons of differentiating neurons. (C) 2004 Elsevier B.V. All rights reserved.
  • K Urase, Y Kouroku, E Fujita, T Momoi
    DEVELOPMENTAL BRAIN RESEARCH 145 (2) 241 - 248 0165-3806 2003/11 [Refereed][Not invited]
     
    Caspase-3-deficient 129/Sv mice show hyperplasia of the brain at embryonic (E) day 10.5-12.5, but caspase-3-deficient C57L/136 mice do not. We examined the relationship between activation of caspase-3 and programmed cell death (PCD) during forebrain development of various mouse strains (129/Sv, ICR, C57L/136, and CBA) using terminal deoxytransferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) and immunostaining with antiserum against the caspase-3 (anti-m3D175) cleavage site. A number of anti-m3D175 positive cells and TUNEL positive cells were detected in the ventral side of the forebrain of 129/Sv and ICR mice at E8.5-9 but not in C57L/136 and CBA mice. Ac-DEVD-MCA cleavage activity, a caspase-3-like activity, also suggests the preferential activation of caspase-3 in the ventral forebrain of ICR mice but not in C57L/136 mice. Developmental changes of TUNEL and anti-m3D175 reactivities were essentially similar during brain morphogenesis of ICR and 129/Sv mice. The number of TUNEL/anti-m3D175 positive cells decreased in the neuroepithelium of the ventral forebrain at E9.5 before generation of the medial ganglionic eminence (MGE). TUNEL and/or anti-m3D175 reactivity was slightly detectable in the MGE at E10.5, from which neuroprogenitor cells follow a tangential migratory route to the cortex. Activation of caspase-9 was also immunohistochemically detected in the ventral forebrain at E8.5-9, suggesting that activation of caspase-3 and caspase-9 occurs in the PCD of this region. Thus, it is likely that decreased cell death in the ventral forebrain of caspase-3- and caspase-9-deficient 129/Sv mice increases the number of neuroprogenitor cells in the MGE, leading to hyperplasia of the forebrain. (C) 2003 Elsevier B.V. All rights reserved.
  • E Fujita, A Soyama, T Momoi
    EXPERIMENTAL CELL RESEARCH 287 (1) 57 - 66 0014-4827 2003/07 [Refereed][Not invited]
     
    RA175, a new immunoglobulin superfamily member, is preferentially expressed during differentiation of P19 embryonic carcinoma (EC) cells induced by retinoic acid. In the present study, we isolated mouse RA175 cDNA in its entirety and showed that RA175 is the mouse ortholog of TSLC1, a tumor suppressor gene in human lung cancer. RA175/TSLC1 was localized in the adherent region of human lung squamous carcinoma cells and in the differentiated P19 EC cells. RA175/TSLC1 showed homophilic trans-interaction activity in a Ca2+-independent manner. RA175/TSLC1 was preferentially expressed in the polarized cells lining the lumen of developing mouse lung epithelium. This suggests that RA175/TSLC1 is a cell adhesion molecule that is acting as a tumor suppressor gene in the metastasis of lung tumors. RA175/TSLC1 may be necessary for cells to remain tightly associated in the epithelium, thereby suppressing metastasis. (C) 2003 Elsevier Science (USA). All rights reserved.
  • T Momoi, E Fujita, K Urase
    NEUROREPORT 14 (1) 111 - 115 0959-4965 2003/01 [Refereed][Not invited]
     
    Caspase-3-deficient 129/Sv mice show hyperplasia of the forebrain at embryonic day (E) 10.5, which suggests that caspase-3-dependent programmed cell death (PCD) plays an essential role in brain morphogenesis prior to neurogenesis. However, little is known about region-specific caspase-3-dependent PCD in the developing forebrain. We examined the PCD region in the early developmental brain at E9.5 by whole mount terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL). In addition to hindbrain, TUNEL-reactivity was detected in the ventral forebrain and in the caudal portion of the front nasal region, just behind the regions expressing fgf-8 and otx-2. It has been shown recently that brain hyperplasia induced by caspase-3-deficiency is mouse strain-dependent; such that brain abnormalities were observed in caspase-3-deficient 129/Sv mice but not in caspase-3-deficient C57BL/6 mice. We examined the caspase-3-dependent PCD in the ventral forebrain of 129/Sv and C57BL/6 mouse embryos (E8.5-9 and E9.5) by double staining of TUNEL and antiserum against the active form of caspase-3 (anti-m3DI75). TUNEL/anti-m3DI75 reactivity in the ventral forebrain was mouse strain-dependent, such that many TUNEL/anti-m3DI75-positive cells were detected in the ventral forebrains of 129/Sv mice, but were not observed in C57BL/6 mice. Thus, it is likely that this region is the site of the strain-specific caspase-3-dependent PCD. A strain-dependent 'modulator' that regulates both caspase-3-dependent and -independent cell death pathways may control PCD in the ventral forebrain at E8.5-9.5.
  • Y Kouroku, E Fujita, A Jimbo, T Kikuchi, T Yamagata, MY Momoi, E Kominami, K Kuida, K Sakamaki, S Yonehara, T Momoi
    HUMAN MOLECULAR GENETICS 11 (13) 1505 - 1515 0964-6906 2002/06 [Refereed][Not invited]
     
    Accumulation of unfolded and malfolded proteins causes endoplasmic reticulum (ER) stress, stimulating unfolded protein response (UPR) and c-Jun N-terminal kinase (JNK) activation and activating caspase-12 located on the ER. Little is known about the relationship between the ER stress and polyglutamine [poly(Q)] aggregates. Poly(Q)(72) repeats [poly(Q)(72)] induced the stimulation of ER stress signals such as JNK activation, upregulation of Grp78/Bip and caspase-12 activation in C2C5 cells. We prepared antiserum against the cleavage site of mouse caspase-12 at D(318) (anti-m12D318), and showed that poly(Q)(72) with perinuclear aggregates, cytoplasmic inclusions and nuclear inclusions stimulated JNK activation and anti-m12D318 immunoreactivity, but poly(Q)(72) with dispersed aggregates and small nuclear aggregates showed a significantly less effect. poly(Q)(72) and poly(Q)(11) dispersed in cytoplasm did not. Anti-m12D318-positive cells showed apoptotic features. Unlike anti-m8D387 immunoreactivity, the anti-m12D318 immunoreactivity was not coaggregated with poly(Q). Ac-IETD-fmk (caspase-8 inhibitor) and Ac-DEVD-CHO (caspase-3 inhibitor) did not prevent the anti-m12D318 immunoreactivity induced by poly(Q)(72) aggregates. Anti-m12D318 immunoreactivity was detected in caspase-8(-/-) and caspase-3(-/-) mouse embryonic fibroblasts expressing poly(Q)(72) aggregates. Thus, caspase-12 was activated by poly(0)72 aggregates via a pathway independent of caspase-8 and caspase-3 activation, and caspase-12 activation was closely associated with poly(Q) aggregate-mediated cell death. Stimulation of ER stress signals may be involved in the pathogenesis of neurodegenerative disorders with poly(Q) expansion.
  • G Fisher, N Lorenzo, H Abe, E Fujita, WH Frey, C Emory, MM Di Fiore, A D'Aniello
    AMINO ACIDS 15 (3) 263 - 269 0939-4451 1998 [Refereed][Not invited]
     
    Free D-Ser, D-Asp and total B-amino acids were significantly higher (p < 0.05) in Alzheimer (AD) ventricular CSF than in normal CSF. There was no significant difference in the total L-amino acids between AD and normal CSF, but L-Gln and L-His were significantly higher (p < 0.05) in AD-CSF, The higher concentrations of these D- and L-amino acids in AD ventricular CSF could reflect the degenerative process that occurs in Alzheimer's brain since ventricular CSF is the repository of amino acids from the brain.


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