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Mol. Cells 2013; 36(1): 82-87

Published online July 31, 2013

https://doi.org/10.1007/s10059-013-0087-9

© The Korean Society for Molecular and Cellular Biology

Generation of Demyelination Models by Targeted Ablation of Oligodendrocytes in the Zebrafish CNS

Ah-Young Chung, Pan-Soo Kim, Suhyun Kim, Eunmi Kim, Dohyun Kim, Inyoung Jeong, Hwan-Ki Kim, Jae-Ho Ryu, Cheol-Hee Kim, June Choi, Jin-Ho Seo, and Hae-Chul Park

1Graduate School of Medicine, Korea University, Ansan 425-707, Korea, 2Gyeonggi Biocenter, Gyeonggi Institute of Science and Technol-ogy Promotion (GSTEP), Suwon 443-270, Korea, 3Genomic Design Bioengineering Company, Daejeon 306-220, Korea, 4Department of Biology and GRAST, Chungnam National University, Daejeon 305-764, Korea, 5Department of Otorhinolaryngology-Head and Neck Surgery, Korea University School of Medicine, Seoul 136-705, Korea, 6Department of Agricultural Biotechnology and Center for Food and Bio Convergence, Seoul National University, Seoul 151-921, Korea, 7These authors contributed equally to this work.

Received: March 18, 2013; Revised: April 22, 2013; Accepted: April 30, 2013

Abstract

Demyelination is the pathological process by which myelin sheaths are lost from around axons, and is usually caused by a direct insult targeted at the oligodendrocytes in the vertebrate central nervous system (CNS). A demyelinated CNS is usually remyelinated by a population of oligodendrocyte progenitor cells, which are widely distributed throughout the adult CNS. However, myelin disruption and remyelination failure affect the normal function of the nervous system, causing human diseases such as multiple sclerosis. In spite of numerous studies aimed at understanding the remyelination process, many questions still remain unanswered. Therefore, to study remyelination mechanisms in vivo, a demyelination animal model was generated using a transgenic zebrafish system in which oligodendrocytes are conditionally ablated in the larval and adult CNS. In this transgenic system, bacterial nitroreductase enzyme (NTR), which converts the prodrug metronidazole (Mtz) into a cytotoxic DNA cross-linking agent, is expressed in oligodendrocyte lineage cells under the control of the mbp and sox10 promoter. Exposure of transgenic zebrafish to Mtz-containing media resulted in rapid ablation of oligodendrocytes and CNS demyelination within 48 h, but removal of Mtz medium led to efficient remyelination of the demyelinated CNS within 7 days. In addition, the demyelination and remyelination processes could be easily observed in living transgenic zebrafish by detecting the fluorescent protein, mCherry, indicating that this transgenic system can be used as a valuable animal model to study the remyelination process in vivo, and to conduct high-throughput primary screens for new drugs that facilitate remyelination.

Keywords CNS, demyelination, nfsB, oligodendrocyte, zebrafish

Article

Research Article

Mol. Cells 2013; 36(1): 82-87

Published online July 31, 2013 https://doi.org/10.1007/s10059-013-0087-9

Copyright © The Korean Society for Molecular and Cellular Biology.

Generation of Demyelination Models by Targeted Ablation of Oligodendrocytes in the Zebrafish CNS

Ah-Young Chung, Pan-Soo Kim, Suhyun Kim, Eunmi Kim, Dohyun Kim, Inyoung Jeong, Hwan-Ki Kim, Jae-Ho Ryu, Cheol-Hee Kim, June Choi, Jin-Ho Seo, and Hae-Chul Park

1Graduate School of Medicine, Korea University, Ansan 425-707, Korea, 2Gyeonggi Biocenter, Gyeonggi Institute of Science and Technol-ogy Promotion (GSTEP), Suwon 443-270, Korea, 3Genomic Design Bioengineering Company, Daejeon 306-220, Korea, 4Department of Biology and GRAST, Chungnam National University, Daejeon 305-764, Korea, 5Department of Otorhinolaryngology-Head and Neck Surgery, Korea University School of Medicine, Seoul 136-705, Korea, 6Department of Agricultural Biotechnology and Center for Food and Bio Convergence, Seoul National University, Seoul 151-921, Korea, 7These authors contributed equally to this work.

Received: March 18, 2013; Revised: April 22, 2013; Accepted: April 30, 2013

Abstract

Demyelination is the pathological process by which myelin sheaths are lost from around axons, and is usually caused by a direct insult targeted at the oligodendrocytes in the vertebrate central nervous system (CNS). A demyelinated CNS is usually remyelinated by a population of oligodendrocyte progenitor cells, which are widely distributed throughout the adult CNS. However, myelin disruption and remyelination failure affect the normal function of the nervous system, causing human diseases such as multiple sclerosis. In spite of numerous studies aimed at understanding the remyelination process, many questions still remain unanswered. Therefore, to study remyelination mechanisms in vivo, a demyelination animal model was generated using a transgenic zebrafish system in which oligodendrocytes are conditionally ablated in the larval and adult CNS. In this transgenic system, bacterial nitroreductase enzyme (NTR), which converts the prodrug metronidazole (Mtz) into a cytotoxic DNA cross-linking agent, is expressed in oligodendrocyte lineage cells under the control of the mbp and sox10 promoter. Exposure of transgenic zebrafish to Mtz-containing media resulted in rapid ablation of oligodendrocytes and CNS demyelination within 48 h, but removal of Mtz medium led to efficient remyelination of the demyelinated CNS within 7 days. In addition, the demyelination and remyelination processes could be easily observed in living transgenic zebrafish by detecting the fluorescent protein, mCherry, indicating that this transgenic system can be used as a valuable animal model to study the remyelination process in vivo, and to conduct high-throughput primary screens for new drugs that facilitate remyelination.

Keywords: CNS, demyelination, nfsB, oligodendrocyte, zebrafish

Mol. Cells
Aug 31, 2022 Vol.45 No.8, pp. 513~602
COVER PICTURE
Cryo-EM structure of human porphyrin transporter ABCB6 (main figure) shows that binding of hemin (inset, magenta) in concert with two glutathione molecules (cyan) primes ABCB6 for high ATP turnover (Kim et al., pp. 575-587).

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