Lactosylceramide synthases encoded by B4galt5 and 6 genes are pivotal for neuronal generation and myelin formation in mice

Toru Yoshihara, Hiroyuki Satake, Toshikazu Nishie, Nozomu Okino, Toshihisa Hatta, Hiroki Otani, Chie Naruse, Hiroshi Suzuki, Kazushi Sugihara, Eikichi Kamimura, Noriyo Tokuda, Keiko Furukawa, Koichi Fururkawa, Makoto Ito, Masahide Asano

研究成果: ジャーナルへの寄稿記事

3 引用 (Scopus)

抄録

It is uncertain which β4-galactosyltransferase (β4GalT; gene name, B4galt), β4GalT-5 and/or β4GalT-6, is responsible for the production of lactosylceramide (LacCer) synthase, which functions in the initial step of ganglioside biosynthesis. Here, we generated conditional B4galt5 knockout (B4galt5 cKO) mice, using Nestin-Cre mice, and crossed these with B4galt6 KO mice to generate B4galt5 and 6 double KO (DKO) mice in the central nervous system (CNS). LacCer synthase activity and major brain gangliosides were completely absent in brain homogenates from the DKO mice, although LacCer synthase activity was about half its normal level in B4galt5 cKO mice and B4galt6 KO mice. The DKO mice were born normally but they showed growth retardation and motor deficits at 2 weeks and died by 4 weeks of age. Histological analyses showed that myelin-associated proteins were rarely found localized in axons in the cerebral cortex, and axonal and myelin formation were remarkably impaired in the spinal cords of the DKO mice. Neuronal cells, differentiated from neurospheres that were prepared from the DKO mice, showed impairments in neurite outgrowth and branch formation, which can be explained by the fact that neurospheres from DKO mice could weakly interact with laminin due to lack of gangliosides, such as GM1a. Furthermore, the neurons were immature and perineuronal nets (PNNs) were poorly formed in DKO cerebral cortices. Our results indicate that LacCer synthase is encoded by B4galt5 and 6 genes in the CNS, and that gangliosides are indispensable for neuronal maturation, PNN formation, and axonal and myelin formation.

元の言語英語
記事番号e1007545
ジャーナルPLoS genetics
14
発行部数8
DOI
出版物ステータス出版済み - 8 2018

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myelin sheath
nervous system
Myelin Sheath
brain
gene
mice
Gangliosides
gangliosides
Genes
maturation
genes
protein
Knockout Mice
Cerebral Cortex
cerebral cortex
Central Nervous System
central nervous system
Galactosyltransferases
Myelin Proteins
UDPgalactose-glucosylceramide galactosyltransferase

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

これを引用

Lactosylceramide synthases encoded by B4galt5 and 6 genes are pivotal for neuronal generation and myelin formation in mice. / Yoshihara, Toru; Satake, Hiroyuki; Nishie, Toshikazu; Okino, Nozomu; Hatta, Toshihisa; Otani, Hiroki; Naruse, Chie; Suzuki, Hiroshi; Sugihara, Kazushi; Kamimura, Eikichi; Tokuda, Noriyo; Furukawa, Keiko; Fururkawa, Koichi; Ito, Makoto; Asano, Masahide.

:: PLoS genetics, 巻 14, 番号 8, e1007545, 08.2018.

研究成果: ジャーナルへの寄稿記事

Yoshihara, T, Satake, H, Nishie, T, Okino, N, Hatta, T, Otani, H, Naruse, C, Suzuki, H, Sugihara, K, Kamimura, E, Tokuda, N, Furukawa, K, Fururkawa, K, Ito, M & Asano, M 2018, 'Lactosylceramide synthases encoded by B4galt5 and 6 genes are pivotal for neuronal generation and myelin formation in mice', PLoS genetics, 巻. 14, 番号 8, e1007545. https://doi.org/10.1371/journal.pgen.1007545
Yoshihara, Toru ; Satake, Hiroyuki ; Nishie, Toshikazu ; Okino, Nozomu ; Hatta, Toshihisa ; Otani, Hiroki ; Naruse, Chie ; Suzuki, Hiroshi ; Sugihara, Kazushi ; Kamimura, Eikichi ; Tokuda, Noriyo ; Furukawa, Keiko ; Fururkawa, Koichi ; Ito, Makoto ; Asano, Masahide. / Lactosylceramide synthases encoded by B4galt5 and 6 genes are pivotal for neuronal generation and myelin formation in mice. :: PLoS genetics. 2018 ; 巻 14, 番号 8.
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title = "Lactosylceramide synthases encoded by B4galt5 and 6 genes are pivotal for neuronal generation and myelin formation in mice",
abstract = "It is uncertain which β4-galactosyltransferase (β4GalT; gene name, B4galt), β4GalT-5 and/or β4GalT-6, is responsible for the production of lactosylceramide (LacCer) synthase, which functions in the initial step of ganglioside biosynthesis. Here, we generated conditional B4galt5 knockout (B4galt5 cKO) mice, using Nestin-Cre mice, and crossed these with B4galt6 KO mice to generate B4galt5 and 6 double KO (DKO) mice in the central nervous system (CNS). LacCer synthase activity and major brain gangliosides were completely absent in brain homogenates from the DKO mice, although LacCer synthase activity was about half its normal level in B4galt5 cKO mice and B4galt6 KO mice. The DKO mice were born normally but they showed growth retardation and motor deficits at 2 weeks and died by 4 weeks of age. Histological analyses showed that myelin-associated proteins were rarely found localized in axons in the cerebral cortex, and axonal and myelin formation were remarkably impaired in the spinal cords of the DKO mice. Neuronal cells, differentiated from neurospheres that were prepared from the DKO mice, showed impairments in neurite outgrowth and branch formation, which can be explained by the fact that neurospheres from DKO mice could weakly interact with laminin due to lack of gangliosides, such as GM1a. Furthermore, the neurons were immature and perineuronal nets (PNNs) were poorly formed in DKO cerebral cortices. Our results indicate that LacCer synthase is encoded by B4galt5 and 6 genes in the CNS, and that gangliosides are indispensable for neuronal maturation, PNN formation, and axonal and myelin formation.",
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AU - Yoshihara, Toru

AU - Satake, Hiroyuki

AU - Nishie, Toshikazu

AU - Okino, Nozomu

AU - Hatta, Toshihisa

AU - Otani, Hiroki

AU - Naruse, Chie

AU - Suzuki, Hiroshi

AU - Sugihara, Kazushi

AU - Kamimura, Eikichi

AU - Tokuda, Noriyo

AU - Furukawa, Keiko

AU - Fururkawa, Koichi

AU - Ito, Makoto

AU - Asano, Masahide

PY - 2018/8

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