TY - JOUR
T1 - Ddx20, DEAD box helicase 20, is essential for the differentiation of oligodendrocyte and maintenance of myelin gene expression
AU - Simankova, Anna
AU - Bizen, Norihisa
AU - Saitoh, Sei
AU - Shibata, Shinsuke
AU - Ohno, Nobuhiko
AU - Abe, Manabu
AU - Sakimura, Kenji
AU - Takebayashi, Hirohide
N1 - Funding Information:
We thank Dr. Michiko Niwa-Kawakita, Dr. Marco Giovannini and RIKEN-BRC for MBPCre-9 transgenic mice, Dr. Corrinne G Lobe and Dr. Andras Nagy for Z/EG transgenic mice, and Dr. Masato Yano and Dr. Katsuhiko Ono for advices. We thank Ms. Atsuko Imai (NIPS) and Ms. Megumi Yatabe (Jichi Medical University) for their technical support. We thank Dr. Lisa Giles from Edanz Group for editing a draft of this manuscript. We thank all members of Takebayashi lab, especially Dr. Yukiko Mori-Ochiai, Dr. Li Zhou, and Mr. Dang Minh Tran for technical supports. H. T. was supported by the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan, Grant-in-Aid for Scientific Research on Innovative Areas “Glial assembly” (18H04939) and “Oscillology” (25117007), Grant-in-Aid for Exploratory Research (16K15168), Grant-in-Aid for Scientific Research (B) (18H02592, 21H02652), grant from the Uehara Memorial Foundation, and Interdisciplinary Joint Research Project from Brain Research Institute, Niigata University. N. B. is supported from Grant-in-Aid for Young Scientists (B) (15K18373, 17K15542) and Grant-in-Aid for Scientific Research (C) (20K07241). H. T. and N. B. were supported by technical support platforms for promoting research of Advanced Bioimaging Support (16H06280) and the Cooperative Study Program of National Institute for Physiological Sciences (18-129, 19-123, 20-129). A. S. is supported by MEXT scholarship and a grant from Kyowakai General Incorporated Foundation.
Funding Information:
We thank Dr. Michiko Niwa‐Kawakita, Dr. Marco Giovannini and RIKEN‐BRC for transgenic mice, Dr. Corrinne G Lobe and Dr. Andras Nagy for transgenic mice, and Dr. Masato Yano and Dr. Katsuhiko Ono for advices. We thank Ms. Atsuko Imai (NIPS) and Ms. Megumi Yatabe (Jichi Medical University) for their technical support. We thank Dr. Lisa Giles from Edanz Group for editing a draft of this manuscript. We thank all members of Takebayashi lab, especially Dr. Yukiko Mori‐Ochiai, Dr. Li Zhou, and Mr. Dang Minh Tran for technical supports. H. T. was supported by the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan, Grant‐in‐Aid for Scientific Research on Innovative Areas “Glial assembly” (18H04939) and “Oscillology” (25117007), Grant‐in‐Aid for Exploratory Research (16K15168), Grant‐in‐Aid for Scientific Research (B) (18H02592, 21H02652), grant from the Uehara Memorial Foundation, and Interdisciplinary Joint Research Project from Brain Research Institute, Niigata University. N. B. is supported from Grant‐in‐Aid for Young Scientists (B) (15K18373, 17K15542) and Grant‐in‐Aid for Scientific Research (C) (20K07241). H. T. and N. B. were supported by technical support platforms for promoting research of Advanced Bioimaging Support (16H06280) and the Cooperative Study Program of National Institute for Physiological Sciences (18‐129, 19‐123, 20‐129). A. S. is supported by MEXT scholarship and a grant from Kyowakai General Incorporated Foundation. MBPCre‐9 Z/EG
Funding Information:
Japan Society for the Promotion of Science, Grant/Award Numbers: 15K18373, 16H06280, 16K15168, 17K15542, 18H02592, 18H04939, 25117007; National Institute for Physiological Sciences, Grant/Award Numbers: 18‐129, 19‐123; Niigata University; Uehara Memorial Foundation; Kyowakai General Incorporated Foundation; MEXT scholarship Funding information
Publisher Copyright:
© 2021 Wiley Periodicals LLC.
PY - 2021/11
Y1 - 2021/11
N2 - Oligodendrocytes form myelin sheaths that surround axons, contributing to saltatory conduction and proper central nervous system (CNS) function. Oligodendrocyte progenitor cells (OPCs) are generated during the embryonic stage and differentiate into myelinating oligodendrocytes postnatally. Ddx20 is a multifunctional, DEAD-box helicase involved in multiple cellular processes, including transcription, splicing, microRNA biogenesis, and translation. Although defects in each of these processes result in abnormal oligodendrocyte differentiation and myelination, the involvement of Ddx20 in oligodendrocyte terminal differentiation remains unknown. To address this question, we used Mbp-Cre mice to generate Ddx20 conditional knockout (cKO) mice to allow for the deletion of Ddx20 from mature oligodendrocytes. Mbp-Cre;Ddx20 cKO mice demonstrated small body sizes, behavioral abnormalities, muscle weakness, and short lifespans, with mortality by the age of 2 months old. Histological analyses demonstrated significant reductions in the number of mature oligodendrocytes and drastic reductions in the expression levels of myelin-associated mRNAs, such as Mbp and Plp at postnatal day 42. The number of OPCs did not change. A thin myelin layer was observed for large-diameter axons in Ddx20 cKO mice, based on electron microscopic analysis. A bromodeoxyuridine (BrdU) labeling experiment demonstrated that terminal differentiation was perturbed from ages 2 weeks to 7 weeks in the CNS of Mbp-Cre;Ddx20 cKO mice. The activation of mitogen-activated protein (MAP) kinase, which promotes myelination, was downregulated in the Ddx20 cKO mice based on immunohistochemical detection. These results indicate that Ddx20 is an essential factor for terminal differentiation of oligodendrocytes and maintenance of myelin gene expression.
AB - Oligodendrocytes form myelin sheaths that surround axons, contributing to saltatory conduction and proper central nervous system (CNS) function. Oligodendrocyte progenitor cells (OPCs) are generated during the embryonic stage and differentiate into myelinating oligodendrocytes postnatally. Ddx20 is a multifunctional, DEAD-box helicase involved in multiple cellular processes, including transcription, splicing, microRNA biogenesis, and translation. Although defects in each of these processes result in abnormal oligodendrocyte differentiation and myelination, the involvement of Ddx20 in oligodendrocyte terminal differentiation remains unknown. To address this question, we used Mbp-Cre mice to generate Ddx20 conditional knockout (cKO) mice to allow for the deletion of Ddx20 from mature oligodendrocytes. Mbp-Cre;Ddx20 cKO mice demonstrated small body sizes, behavioral abnormalities, muscle weakness, and short lifespans, with mortality by the age of 2 months old. Histological analyses demonstrated significant reductions in the number of mature oligodendrocytes and drastic reductions in the expression levels of myelin-associated mRNAs, such as Mbp and Plp at postnatal day 42. The number of OPCs did not change. A thin myelin layer was observed for large-diameter axons in Ddx20 cKO mice, based on electron microscopic analysis. A bromodeoxyuridine (BrdU) labeling experiment demonstrated that terminal differentiation was perturbed from ages 2 weeks to 7 weeks in the CNS of Mbp-Cre;Ddx20 cKO mice. The activation of mitogen-activated protein (MAP) kinase, which promotes myelination, was downregulated in the Ddx20 cKO mice based on immunohistochemical detection. These results indicate that Ddx20 is an essential factor for terminal differentiation of oligodendrocytes and maintenance of myelin gene expression.
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U2 - 10.1002/glia.24058
DO - 10.1002/glia.24058
M3 - Article
C2 - 34231259
AN - SCOPUS:85109160963
VL - 69
SP - 2559
EP - 2574
JO - GLIA
JF - GLIA
SN - 0894-1491
IS - 11
ER -