Glial cell degeneration and hypomyelination caused by overexpression of myelin proteolipid protein gene

Tetsushi Kagawa, Kazuhiro Ikenaka, Yoshiro Inoue, Shigeki Kuriyama, Tadasu Tsujii, Junji Nakao, Kazunori Nakajima, Jun Aruga, Hideyuki Okano, Katsuhiko Mikoshiba

Research output: Contribution to journalArticle

220 Citations (Scopus)

Abstract

Myelin proteolipid protein (PLP), the major myelin protein in the CNS, has been thought to function in myelin assembly. Thus, mutations within the gene coding for PLP (Plp) cause hypomyelination, such as the jimpy phenotype in mice and Pelizaeus-Merzbacher disease in humans. However, these mutants often exhibit premature death of oligodendrocytes, which form CNS myelin. To elucidate the functional roles of Pip gene products in the maturation and/or survival of oligodendrocytes, we produced transgenic mice overexpressing the Plp gene by introducing extra wild-type mouse Pip genes. Surprisingly, transgenic mice bearing 4 more Plp genes exhibited dysmyelination in the CNS, whereas those with 2 more Plp genes showed normal myelination at an early age (3 weeks after birth), but later developed demyelination. Overexpression of the Plp gene resulted in arrested maturation of oligodendrocytes, and the severity of arrest was dependent on the extent of overexpression. Overexpression also led to oligodendrocyte cell death, apparently caused by abnormal swelling of the Golgi apparatus. Thus, tight regulation of Plpgene expression is necessary for normal oligodendrocyte differentiation and survival, and its overexpression can be the cause of both dys- and demyelination.

Original languageEnglish
Pages (from-to)427-442
Number of pages16
JournalNeuron
Volume13
Issue number2
DOIs
Publication statusPublished - 1994
Externally publishedYes

Fingerprint

Myelin Proteolipid Protein
Neuroglia
Oligodendroglia
Genes
Demyelinating Diseases
Myelin Sheath
Transgenic Mice
Pelizaeus-Merzbacher Disease
Proteolipids
Myelin Proteins
Premature Mortality
Golgi Apparatus
Cell Death
Parturition
Phenotype
Mutation
Survival

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Kagawa, T., Ikenaka, K., Inoue, Y., Kuriyama, S., Tsujii, T., Nakao, J., ... Mikoshiba, K. (1994). Glial cell degeneration and hypomyelination caused by overexpression of myelin proteolipid protein gene. Neuron, 13(2), 427-442. https://doi.org/10.1016/0896-6273(94)90358-1

Glial cell degeneration and hypomyelination caused by overexpression of myelin proteolipid protein gene. / Kagawa, Tetsushi; Ikenaka, Kazuhiro; Inoue, Yoshiro; Kuriyama, Shigeki; Tsujii, Tadasu; Nakao, Junji; Nakajima, Kazunori; Aruga, Jun; Okano, Hideyuki; Mikoshiba, Katsuhiko.

In: Neuron, Vol. 13, No. 2, 1994, p. 427-442.

Research output: Contribution to journalArticle

Kagawa, T, Ikenaka, K, Inoue, Y, Kuriyama, S, Tsujii, T, Nakao, J, Nakajima, K, Aruga, J, Okano, H & Mikoshiba, K 1994, 'Glial cell degeneration and hypomyelination caused by overexpression of myelin proteolipid protein gene', Neuron, vol. 13, no. 2, pp. 427-442. https://doi.org/10.1016/0896-6273(94)90358-1
Kagawa, Tetsushi ; Ikenaka, Kazuhiro ; Inoue, Yoshiro ; Kuriyama, Shigeki ; Tsujii, Tadasu ; Nakao, Junji ; Nakajima, Kazunori ; Aruga, Jun ; Okano, Hideyuki ; Mikoshiba, Katsuhiko. / Glial cell degeneration and hypomyelination caused by overexpression of myelin proteolipid protein gene. In: Neuron. 1994 ; Vol. 13, No. 2. pp. 427-442.
@article{f4d173f3af2745e8bf6c1570aca85b2a,
title = "Glial cell degeneration and hypomyelination caused by overexpression of myelin proteolipid protein gene",
abstract = "Myelin proteolipid protein (PLP), the major myelin protein in the CNS, has been thought to function in myelin assembly. Thus, mutations within the gene coding for PLP (Plp) cause hypomyelination, such as the jimpy phenotype in mice and Pelizaeus-Merzbacher disease in humans. However, these mutants often exhibit premature death of oligodendrocytes, which form CNS myelin. To elucidate the functional roles of Pip gene products in the maturation and/or survival of oligodendrocytes, we produced transgenic mice overexpressing the Plp gene by introducing extra wild-type mouse Pip genes. Surprisingly, transgenic mice bearing 4 more Plp genes exhibited dysmyelination in the CNS, whereas those with 2 more Plp genes showed normal myelination at an early age (3 weeks after birth), but later developed demyelination. Overexpression of the Plp gene resulted in arrested maturation of oligodendrocytes, and the severity of arrest was dependent on the extent of overexpression. Overexpression also led to oligodendrocyte cell death, apparently caused by abnormal swelling of the Golgi apparatus. Thus, tight regulation of Plpgene expression is necessary for normal oligodendrocyte differentiation and survival, and its overexpression can be the cause of both dys- and demyelination.",
author = "Tetsushi Kagawa and Kazuhiro Ikenaka and Yoshiro Inoue and Shigeki Kuriyama and Tadasu Tsujii and Junji Nakao and Kazunori Nakajima and Jun Aruga and Hideyuki Okano and Katsuhiko Mikoshiba",
year = "1994",
doi = "10.1016/0896-6273(94)90358-1",
language = "English",
volume = "13",
pages = "427--442",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "2",

}

TY - JOUR

T1 - Glial cell degeneration and hypomyelination caused by overexpression of myelin proteolipid protein gene

AU - Kagawa, Tetsushi

AU - Ikenaka, Kazuhiro

AU - Inoue, Yoshiro

AU - Kuriyama, Shigeki

AU - Tsujii, Tadasu

AU - Nakao, Junji

AU - Nakajima, Kazunori

AU - Aruga, Jun

AU - Okano, Hideyuki

AU - Mikoshiba, Katsuhiko

PY - 1994

Y1 - 1994

N2 - Myelin proteolipid protein (PLP), the major myelin protein in the CNS, has been thought to function in myelin assembly. Thus, mutations within the gene coding for PLP (Plp) cause hypomyelination, such as the jimpy phenotype in mice and Pelizaeus-Merzbacher disease in humans. However, these mutants often exhibit premature death of oligodendrocytes, which form CNS myelin. To elucidate the functional roles of Pip gene products in the maturation and/or survival of oligodendrocytes, we produced transgenic mice overexpressing the Plp gene by introducing extra wild-type mouse Pip genes. Surprisingly, transgenic mice bearing 4 more Plp genes exhibited dysmyelination in the CNS, whereas those with 2 more Plp genes showed normal myelination at an early age (3 weeks after birth), but later developed demyelination. Overexpression of the Plp gene resulted in arrested maturation of oligodendrocytes, and the severity of arrest was dependent on the extent of overexpression. Overexpression also led to oligodendrocyte cell death, apparently caused by abnormal swelling of the Golgi apparatus. Thus, tight regulation of Plpgene expression is necessary for normal oligodendrocyte differentiation and survival, and its overexpression can be the cause of both dys- and demyelination.

AB - Myelin proteolipid protein (PLP), the major myelin protein in the CNS, has been thought to function in myelin assembly. Thus, mutations within the gene coding for PLP (Plp) cause hypomyelination, such as the jimpy phenotype in mice and Pelizaeus-Merzbacher disease in humans. However, these mutants often exhibit premature death of oligodendrocytes, which form CNS myelin. To elucidate the functional roles of Pip gene products in the maturation and/or survival of oligodendrocytes, we produced transgenic mice overexpressing the Plp gene by introducing extra wild-type mouse Pip genes. Surprisingly, transgenic mice bearing 4 more Plp genes exhibited dysmyelination in the CNS, whereas those with 2 more Plp genes showed normal myelination at an early age (3 weeks after birth), but later developed demyelination. Overexpression of the Plp gene resulted in arrested maturation of oligodendrocytes, and the severity of arrest was dependent on the extent of overexpression. Overexpression also led to oligodendrocyte cell death, apparently caused by abnormal swelling of the Golgi apparatus. Thus, tight regulation of Plpgene expression is necessary for normal oligodendrocyte differentiation and survival, and its overexpression can be the cause of both dys- and demyelination.

UR - http://www.scopus.com/inward/record.url?scp=0028133486&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028133486&partnerID=8YFLogxK

U2 - 10.1016/0896-6273(94)90358-1

DO - 10.1016/0896-6273(94)90358-1

M3 - Article

C2 - 7520255

AN - SCOPUS:0028133486

VL - 13

SP - 427

EP - 442

JO - Neuron

JF - Neuron

SN - 0896-6273

IS - 2

ER -