Ceramide galactosyltransferase expression is regulated positively by Nkx2.2 and negatively by OLIG2

Kyohei Okahara, Yasuhiko Kizuka, Shinobu Kitazume, Fumi Ota, Kazuki Nakajima, Yoshio Hirabayashi, Motoko Maekawa, Takeo Yoshikawa, Naoyuki Taniguchi

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Myelin, a multilamellar structure extended from oligodendrocytes or Schwann cells, plays a critical role in maintenance of neuronal function, and damage or loss of myelin causes demyelinating diseases such as multiple sclerosis. For precise alignment of the myelin sheath, there is a requirement for expression of galactosylceramide (GalCer), a major glycosphingolipid in myelin. Synthesis of GalCer is strictly limited in oligodendrocytes in a developmental stage-specific manner. Ceramide galactosyltransferase (CGT), a key enzyme for biosynthesis of GalCer, exhibits restricted expression in oligodendrocytes but the mechanism is poorly understood. Based on our assumption that particular oligodendrocyte-lineagespecific transcription factors regulate CGT expression, we co-expressed a series of candidate transcription factors with the human CGT promoter-driving luciferase expression in oligodendroglioma cells to measure the promoter activity. We found that Nkx2.2 strongly activated the CGT promoter. In addition, we identified a novel repressive DNA element in the first intron of CGT and OLIG2, an oligodendrocyte-specific transcription factor, as a binding protein of this element. Moreover, overexpression of OLIG2 completely canceled the activating effect of Nkx2.2 on CGT promoter activity. Expression of CGT mRNA was also upregulated by Nkx2.2, but this upregulation was cancelled by co-expression of OLIG2 with Nkx2.2. Our study suggests that CGT expression is controlled by balanced expression of the negative modulator OLIG2 and positive regulator Nkx2.2, providing new insights into how expression of GalCer is tightly regulated in cell-type- and stage-specific manners.

Original languageEnglish
Pages (from-to)926-934
Number of pages9
JournalGlycobiology
Volume24
Issue number10
DOIs
Publication statusPublished - 01-10-2014

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N-Acylsphingosine Galactosyltransferase
Galactosylceramides
Oligodendroglia
Myelin Sheath
Transcription Factors
Oligodendroglioma
Glycosphingolipids
Schwann Cells
Biosynthesis
Demyelinating Diseases
Luciferases
Introns
Modulators
Multiple Sclerosis
Carrier Proteins
Up-Regulation
Cells
Maintenance

All Science Journal Classification (ASJC) codes

  • Biochemistry

Cite this

Okahara, K., Kizuka, Y., Kitazume, S., Ota, F., Nakajima, K., Hirabayashi, Y., ... Taniguchi, N. (2014). Ceramide galactosyltransferase expression is regulated positively by Nkx2.2 and negatively by OLIG2. Glycobiology, 24(10), 926-934. https://doi.org/10.1093/glycob/cwu042
Okahara, Kyohei ; Kizuka, Yasuhiko ; Kitazume, Shinobu ; Ota, Fumi ; Nakajima, Kazuki ; Hirabayashi, Yoshio ; Maekawa, Motoko ; Yoshikawa, Takeo ; Taniguchi, Naoyuki. / Ceramide galactosyltransferase expression is regulated positively by Nkx2.2 and negatively by OLIG2. In: Glycobiology. 2014 ; Vol. 24, No. 10. pp. 926-934.
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Okahara, K, Kizuka, Y, Kitazume, S, Ota, F, Nakajima, K, Hirabayashi, Y, Maekawa, M, Yoshikawa, T & Taniguchi, N 2014, 'Ceramide galactosyltransferase expression is regulated positively by Nkx2.2 and negatively by OLIG2', Glycobiology, vol. 24, no. 10, pp. 926-934. https://doi.org/10.1093/glycob/cwu042

Ceramide galactosyltransferase expression is regulated positively by Nkx2.2 and negatively by OLIG2. / Okahara, Kyohei; Kizuka, Yasuhiko; Kitazume, Shinobu; Ota, Fumi; Nakajima, Kazuki; Hirabayashi, Yoshio; Maekawa, Motoko; Yoshikawa, Takeo; Taniguchi, Naoyuki.

In: Glycobiology, Vol. 24, No. 10, 01.10.2014, p. 926-934.

Research output: Contribution to journalArticle

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T1 - Ceramide galactosyltransferase expression is regulated positively by Nkx2.2 and negatively by OLIG2

AU - Okahara, Kyohei

AU - Kizuka, Yasuhiko

AU - Kitazume, Shinobu

AU - Ota, Fumi

AU - Nakajima, Kazuki

AU - Hirabayashi, Yoshio

AU - Maekawa, Motoko

AU - Yoshikawa, Takeo

AU - Taniguchi, Naoyuki

PY - 2014/10/1

Y1 - 2014/10/1

N2 - Myelin, a multilamellar structure extended from oligodendrocytes or Schwann cells, plays a critical role in maintenance of neuronal function, and damage or loss of myelin causes demyelinating diseases such as multiple sclerosis. For precise alignment of the myelin sheath, there is a requirement for expression of galactosylceramide (GalCer), a major glycosphingolipid in myelin. Synthesis of GalCer is strictly limited in oligodendrocytes in a developmental stage-specific manner. Ceramide galactosyltransferase (CGT), a key enzyme for biosynthesis of GalCer, exhibits restricted expression in oligodendrocytes but the mechanism is poorly understood. Based on our assumption that particular oligodendrocyte-lineagespecific transcription factors regulate CGT expression, we co-expressed a series of candidate transcription factors with the human CGT promoter-driving luciferase expression in oligodendroglioma cells to measure the promoter activity. We found that Nkx2.2 strongly activated the CGT promoter. In addition, we identified a novel repressive DNA element in the first intron of CGT and OLIG2, an oligodendrocyte-specific transcription factor, as a binding protein of this element. Moreover, overexpression of OLIG2 completely canceled the activating effect of Nkx2.2 on CGT promoter activity. Expression of CGT mRNA was also upregulated by Nkx2.2, but this upregulation was cancelled by co-expression of OLIG2 with Nkx2.2. Our study suggests that CGT expression is controlled by balanced expression of the negative modulator OLIG2 and positive regulator Nkx2.2, providing new insights into how expression of GalCer is tightly regulated in cell-type- and stage-specific manners.

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