Restoration of the defect in radial glial fiber migration and cortical plate organization in a brain organoid model of Fukuyama muscular dystrophy
Mariko Taniguchi-Ikeda,
Michiyo Koyanagi-Aoi,
Tatsuo Maruyama,
Toru Takaori,
Akiko Hosoya,
Hiroyuki Tezuka,
Shotaro Nagase,
Takuma Ishihara,
Taisuke Kadoshima,
Keiko Muguruma,
Keiko Ishigaki,
Hidetoshi Sakurai,
Akira Mizoguchi,
Bennett G. Novitch,
Tatsushi Toda,
Momoko Watanabe,
Takashi Aoi
Affiliations
Mariko Taniguchi-Ikeda
Department of Clinical Genetics, Fujita Health University Hospital, 1-98 Dengakugakubo, Kutsukake-chou, Toyoake, Aichi 470-1192, Japan; Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan; Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan; Corresponding author
Michiyo Koyanagi-Aoi
Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, Kobe, Hyogo 650-0017, Japan; Department of iPS Cell Applications, Graduate School of Medicine, Kobe University, Kobe, Hyogo 650-0017, Japan; Center for Human Resource Development for Regenerative Medicine, Kobe University Hospital, Kobe, Hyogo 650-0017, Japan
Tatsuo Maruyama
Department of Chemical Science and Engineering, Graduate School of Engineering, Kobe University, Kobe, Hyogo 657-8501, Japan
Toru Takaori
Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan; Department of Pediatrics, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan
Akiko Hosoya
Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, Kobe, Hyogo 650-0017, Japan; Department of iPS Cell Applications, Graduate School of Medicine, Kobe University, Kobe, Hyogo 650-0017, Japan; Center for Human Resource Development for Regenerative Medicine, Kobe University Hospital, Kobe, Hyogo 650-0017, Japan
Hiroyuki Tezuka
Department of Cellular Function Analysis, Research Promotion and Support Headquarters, Fujita Health University, Toyoake, Aichi 470-1192, Japan
Shotaro Nagase
Asubio Pharma Co., Ltd., Kobe, Hyogo 650-0047, Japan
Takuma Ishihara
Innovative and Clinical Research Promotion Center, Gifu University Hospital, Yanagido, Gifu 501-1194, Japan
Taisuke Kadoshima
Asubio Pharma Co., Ltd., Kobe, Hyogo 650-0047, Japan
Keiko Muguruma
Laboratory for Cell Asymmetry, RIKEN Center for Developmental Biology, Kobe, Hyogo 650-0047, Japan; Department of iPS Cell Applied Medicine, Graduate School of Medicine, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
Keiko Ishigaki
Department of Pediatrics, Tokyo Women’s Medical University, School of Medicine, Shinjuku-ku, Tokyo 162-8666, Japan
Hidetoshi Sakurai
Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan
Akira Mizoguchi
Department of Personalized Cancer Immunotherapy, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan
Bennett G. Novitch
Department of Neurobiology, David Geffen School of Medicine at the University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA, USA; Intellectual and Developmental Disabilities Research Center, UCLA, Los Angeles, CA 90095, USA
Tatsushi Toda
Department of Neurology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8655, Japan
Momoko Watanabe
Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA; Sue & Bill Gross Stem Cell Research Center, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA
Takashi Aoi
Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, Kobe, Hyogo 650-0017, Japan; Department of iPS Cell Applications, Graduate School of Medicine, Kobe University, Kobe, Hyogo 650-0017, Japan; Center for Human Resource Development for Regenerative Medicine, Kobe University Hospital, Kobe, Hyogo 650-0017, Japan
Summary: Fukuyama congenital muscular dystrophy (FCMD) is a severe, intractable genetic disease that affects the skeletal muscle, eyes, and brain and is attributed to a defect in alpha dystroglycan (αDG) O-mannosyl glycosylation. We previously established disease models of FCMD; however, they did not fully recapitulate the phenotypes observed in human patients. In this study, we generated induced pluripotent stem cells (iPSCs) from a human FCMD patient and differentiated these cells into three-dimensional brain organoids and skeletal muscle. The brain organoids successfully mimicked patient phenotypes not reliably reproduced by existing models, including decreased αDG glycosylation and abnormal radial glial (RG) fiber migration. The basic polycyclic compound Mannan-007 (Mn007) restored αDG glycosylation in the brain and muscle models tested and partially rescued the abnormal RG fiber migration observed in cortical organoids. Therefore, our study underscores the importance of αDG O-mannosyl glycans for normal RG fiber architecture and proper neuronal migration in corticogenesis.
