TY - JOUR
T1 - Restoration of the defect in radial glial fiber migration and cortical plate organization in a brain organoid model of Fukuyama muscular dystrophy
AU - Taniguchi-Ikeda, Mariko
AU - Koyanagi-Aoi, Michiyo
AU - Maruyama, Tatsuo
AU - Takaori, Toru
AU - Hosoya, Akiko
AU - Tezuka, Hiroyuki
AU - Nagase, Shotaro
AU - Ishihara, Takuma
AU - Kadoshima, Taisuke
AU - Muguruma, Keiko
AU - Ishigaki, Keiko
AU - Sakurai, Hidetoshi
AU - Mizoguchi, Akira
AU - Novitch, Bennett G.
AU - Toda, Tatsushi
AU - Watanabe, Momoko
AU - Aoi, Takashi
N1 - Funding Information:
We would like to thank Kana Sugahara, S.N. Tomoko Yashiro, Aya Kubota, Michiko Ujihara, Ayaka Nishiyama, Ryou Yoshida, Yuko Takeuchi, Rena Takeda, Tatsuro Ikeda, Aasami Kita, Yu Furuno, Akiko Kojima, Katsuyuki Yokoi, Khaledian Behnoush and Takema Kato for technical support. We would like to thank Drs. Hiroshi Manya, Keiichiro Inamori, and Akitsu Hotta, Professors Fumio Matsuzaki, Ichiro Morioka, Yoshiki Yamaguchi, Kazumoto Iijima, Tamao Endo, and Naoyuki Taniguchi for their valuable comments. We would like to thank Drs. Helena A. Popiel and Allison C. Sharrow for editing and proofreading the manuscript. This research was supported by grants from the Japan Agency for Medical Research and Development (17ek0109193h0002 to MTI, TA, and KM; 20ek0109318h0003 to MTI, MKA, TM, and TA; 20ek0109405h0002 to HS, and MTI; 18ek0109249h0002 to TT, MTI, and KI, 21bm0804028h0001 to MTI, MKA), Grants-in-Aid for Scientific Research (18K07790 to MTI and IK, 21H02885 to MTI, TA, MKA, TM, and KI), The Naito Foundation (to MTI), Japan Intractable Disease Foundation (to MTI), Takeda Science Foundation (to MTI), Houansya Foundation (to MTI), Akira Sakagami Fund for Research and Education from Kobe University Graduate School of Medicine (to TA), and Research Assistance Funds from the General Incorporated Association Shinryokukai (to TA), National Institute of Health (R01NS089817, R01DA051897, and P50HD103557 to BGN; K99/R00HD096105 to MW), the California Institute for Regenerative Medicine (DISC1-08819 to BGN), and the UCLA Broad Stem Cell Research Center (BSCRC) to BGN, and training awards provided by the UCLA BSCRC, UCLA Brain Research Institute, and the Uehara Memorial Foundation to MW. Conceptualization: MTI, TA; Methodology: MTI, TA, MKA TM HS SN, TT HT TK; Validation: MKA, HS, TT, HT; Investigation: MTI, MKA, AH, TA; Visualization: MTI, AH, AM, KI; Statistical Analysis: T.I; Resources: AM, KI; Funding acquisition: MTI, TA, TT; Project administration: MTI, TA; Supervision: MW, BGN, KM, TT; Writing – original draft: MTI, TA, MW, MKA, and TM; Writing – review & editing: MTI, TA, MKA, and MW. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Funding Information:
We would like to thank Kana Sugahara, S.N., Tomoko Yashiro, Aya Kubota, Michiko Ujihara, Ayaka Nishiyama, Ryou Yoshida, Yuko Takeuchi, Rena Takeda, Tatsuro Ikeda, Aasami Kita, Yu Furuno, Akiko Kojima, Katsuyuki Yokoi, Khaledian Behnoush and Takema Kato for technical support. We would like to thank Drs. Hiroshi Manya, Keiichiro Inamori, and Akitsu Hotta, Professors Fumio Matsuzaki, Ichiro Morioka, Yoshiki Yamaguchi, Kazumoto Iijima, Tamao Endo, and Naoyuki Taniguchi for their valuable comments. We would like to thank Drs. Helena A. Popiel and Allison C. Sharrow for editing and proofreading the manuscript. This research was supported by grants from the Japan Agency for Medical Research and Development ( 17ek0109193h0002 to MTI, TA, and KM; 20ek0109318h0003 to MTI, MKA, TM, and TA; 20ek0109405h0002 to HS, and MTI; 18ek0109249h0002 to TT, MTI, and KI, 21bm0804028h0001 to MTI, MKA), Grants-in-Aid for Scientific Research ( 18K07790 to MTI and IK, 21H02885 to MTI, TA, MKA, TM, and KI), The Naito Foundation (to MTI), Japan Intractable Disease Foundation (to MTI), Takeda Science Foundation (to MTI), Houansya Foundation (to MTI), Akira Sakagami Fund for Research and Education from Kobe University Graduate School of Medicine (to TA), and Research Assistance Funds from the General Incorporated Association Shinryokukai (to TA), National Institute of Health ( R01NS089817 , R01DA051897 , and P50HD103557 to BGN; K99/R00HD096105 to MW), the California Institute for Regenerative Medicine ( DISC1-08819 to BGN), and the UCLA Broad Stem Cell Research Center (BSCRC) to BGN, and training awards provided by the UCLA BSCRC, UCLA Brain Research Institute , and the Uehara Memorial Foundation to MW.
Publisher Copyright:
© 2021 The Author(s)
PY - 2021/10/22
Y1 - 2021/10/22
N2 - 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.
AB - 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.
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U2 - 10.1016/j.isci.2021.103140
DO - 10.1016/j.isci.2021.103140
M3 - Article
AN - SCOPUS:85120642045
VL - 24
JO - iScience
JF - iScience
SN - 2589-0042
IS - 10
M1 - 103140
ER -