研究者詳細 - 岡野　栄之

論文 - 岡野　栄之

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Disorders in myelination in the twitcher mutant

Mikoshiba Katsuhiko, Fujishiro Masatoshi, Kohsaka Shinichi, Okano Hideyuki, Takamatsu Ken, Tsukada Yasuzo

Neurochemical Research 10 （ 8 ） 1129 - 1141 1985年08月

ISSN 0364-3190

The twitcher is an autosomal recessive mutant mouse characterized by absence of galactosylceramidase. The twitcher shows clinical and histological features similar to those of human Krabbe-type leukodystrophy. We here present the results of a neurochemical and immunohistochemical analysis of the twitcher. Electrophoretic analysis revealed that in the particulate fraction of the spinal cord, myelin basic proteins (MBP) and proteolipid protein were decreased, and in the sciatic nerve fibers, PO protein, X, Y and MBP were clearly decreased. 2′,3′-Cyclic nucleotide 3′-phosphodiesterase (CNPase) activities of the pallium cerebri, brain stem and spinal cord of the twitcher were about 20% less than those of the control. However, in the sciatic nerve, the activity was half that of the control. Immunohistochemical studies were carried out by means of antisera against MBP and CNPase. There were clear patches indicating both MBP- and CNPase-negative reactions in the white matter of the central nervous system from the twitcher. The reaction on the section of sciatic nerve fibers from the twitcher showed a positive reaction only in a very limited number of fibers with both MBP and CNPase antisera. A clear astrocytic hypertrophy was detected by the antiserum against glial fibrillary acidic protein (GFAP). Even in the grey matter of the cerebral cortex, strong GFAP-positive astrocytes were clearly observed. © 1985 Plenum Publishing Corporation.

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Molecular genetic analysis of myelin-deficient mice: shiverer mutant mice show deletion in gene(s) coding for myelin basic protein.

1) Kimura M, Inoko H, Katsuki M, Ando, A, Sato T, Hirose T, Takashima H, Inayama S, Okano H, Takamatsu K, Mikoshiba K, Tsukada Y, Watanabe I.

Journal of Neurochemistry 44 692 - 696 1985年

研究論文（学術雑誌）, 共著, 査読有り

The gene expression of myelin basic proteins (MBPs) in shiverer mutant mice was investigated by the Northern and Southern hybridization techniques. In the control mice RNA molecules from the brains which were about 2,300 nucleotides in length were hybridized to cDNA of 1.8 kb encoding for a mouse MBP, but RNA from the brains of 3-week-old shiverer mutant mice contained no detectable amount of MBP transcripts hybridizing to this probe. Moreover the shiverer mutant mice lost several restriction fragments that hybridized to the same probe in the control mice when each of the five restriction enzymes, i.e., HindIII, PstI, PvuII, AccI, and StuI, was used. These data suggest that the shiverer mutation may correspond to the deletion of a large portion of MBP exon(s) in the gene, and this deletion causes inefficient transcription leading to the depletion of MBPs in the myelin and the dysmyelination observed in these mice.

P₄₀₀ protein characteristic to Purkinje cells and related proteins in cerebella from neuropathological mutant mice

Mikoshiba K., Okano H., Tsukada Y.

Developmental Neuroscience 7 （ 3 ） 179 - 187 1985年

ISSN 0378-5866

P₄₀₀ protein has been found in the cerebellum and localizes to Purkinje cells. It is a glycoprotein and reacts with plant lectins. Autoradiographic patterns of the protein profiles of mutant mice cerebella after intracranial injections of ¹⁴C-leucine were analyzed. P₄₀₀ protein was one of the dominant proteins labeled in the control cerebellum. No incorporation of ¹⁴C-leucine to the position of P₄₀₀ protein was found in the nervous and pcd mutant mice where no Purkinje cells and no P₄₀₀ protein are present. P₄₀₀ protein in weaver cerebellum was labelled more intensely than that in the control. In the staggerer mice, where dendritic arborization of Purkinje cell is poor and no spines are formed on the dendrites, no P₄₀₀ protein was found and no ¹⁴C-leucine incorporation was observed to the position of P₄₀₀ protein, suggesting that staggerer is a mutation where no P₄₀₀ protein accumulated in the fractions being studied. P₄₀₀ protein was phosphorylated independently of the presence of Ca²⁺. Among the proteins of the isolated Purkinje cells, P₄₀₀ protein was one of the major proteins phosphorylated.

Immunohistochemical, biochemical and electron microscopic analysis of myelin formation in the central nervous system of myelin deficient (mld) mutant mice.

Mikoshiba K., Okano H., Inoue Y., Fujishiro M., Takamatsu K., Lachapelle F., Baumann N., Tsukada Y.

Brain Research 432 （ 1 ） 111 - 121 1987年09月

ISSN 0006-8993

Myelin deficiency (mld) is an autosomal recessive mutation in mice and is considered to be allelic to the shiverer (shi) mutation. Mld mice are characterized by hypomyelination of the central nervous system (CNS). They show typical symptoms such as tremor, tonic convulsion and ataxic movement. Subcellular fractionation of the CNS revealed that the MBP bands were greatly decreased in the P2A (myelin) fraction and the total content of myelin basic protein (MBP) was much lower than that in the control in all parts of the CNS. Sections from mld mice were examined by immunohistochemical tests with MBP antiserum, and a mosaic expression of MBP was found in the myelin of the mld mice. Since the major dense line is considered to be composed mainly of MBP, we investigated the myelin of mld mice by electron microscopy and found that there were 3 types of myelin: (1) a normal type compact myelin with a major dense line, (2) a shiverer-type myelin with no major dense line, and (3) a mixed-type myelin, in which within a myelin lamella the major dense line abruptly changes to cytoplasm of oligodendrocytes.

Inefficient transcription of the myelin basic protein gene possibly causes hypomyelination in myelin-deficient mutant mice

Okano H., Miura M., Moriguchi A., Ikenaka K., Tsukada Y., Mikoshiba K.

Journal of Neurochemistry 48 （ 2 ） 470 - 476 1987年

ISSN 0022-3042

A hereditary dysmyelination mutation, named myelin deficient (mld), is considered to be allelic to shiverer, a deletion mutation of the myelin basic protein (MBP) gene. The present study showed that MBP expression is greatly reduced in mld, but that it is still detectable. Northern blot analysis revealed that the pronounced decrease in the MBP level in mld resulted from a reduced mRNA level and was not caused by deletion of a large portion of the MBP gene as in shiverer. Southern blod studies with BamHI-digested chromosomal DNA suggested some part of the MBP gene, at least the 5'-portion, was duplicated in mld. These results indicated that the mld and shiverer mutations were different from each other, even though genetic allelism between the two was reconfirmed. We also examined the developmental pattern of the gene expression of MBP and that of another protein, myelin proteolipid protein (PLP), specifically expressed in the oligodendrocyte, in mld by RNA dot blot study. The mRNA level of MBP in mld was greatly reduced during the active myelination stages, gradually increasing and remaining constant in the later stages. The PLP-mRNA content in mld was almost normal (60-80% that of control) at any stage of development. All these findings imply that the primary defect in mld is due to reduced transcriptional activity of the MBP gene.

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The fifth exon of the myelin proteolipid protein-coding gene is not utilized in the brain of jimpy mutant mice

Moriguchi Akira, Ikenaka Kazuhiro, Furuichi Teiichi, Okano Hideyuki, Iwasaki Yasuno, Mikoshiba Katsuhiko

Gene 55 （ 2-3 ） 333 - 337 1987年

ISSN 0378-1119

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Recombination within the upstream gene of duplicated myelin basic protein genes of myelin deficient shimld mouse results in the production of antisense RNA.

Okano H., Ikenaka K., Mikoshiba K.

EMBO Journal 7 （ 11 ） 3407 - 3412 1988年11月

ISSN 0261-4189

The myelin deficient shimld mouse is an autosomal recessive mutant, characterized by hypomyelination in the central nervous system. The expression of the myelin basic protein (MBP) gene is inhibited transcriptionally. The MBP gene is duplicated tandemly in mld, and exons 3 to 7 of the upstream copy is inverted. In the present studies, we determined the approximate position of the 5' boundary and the nucleotide sequence surrounding the 3' boundary of the inversion and found a number of sequences homologous to the switching regions of mouse immunoglobulin heavy chain gene and J regions of human T cell receptor genes. Antisense RNA complementary to exons 3 and 7, which correspond to the inverted segment, was detected by RNase protection studies. This abnormal transcript was also shown to elongate through the inverted segment to reach the transcription initiation site of the downstream gene.

Central myelin in the first hybrid mice produced by intercrossing homozygotes of shiverer and myelin-deficient mutants

Inoue Yoshiro, Takahashi Shiro, Takayama Chitoshi, Inoue Kaoru, Okano Hideyuki, Mikoshiba Katsuhiko

Brain Research 449 （ 1-2 ） 271 - 280 1988年05月

ISSN 0006-8993

The first hybrid mice ('shiverer*mld' mice) produced by intercrossing the homozygotes of the shiverer (BALB/c strain) and mld (MDB/Dt strain) were used for investigating the fine structure of the myelin lamellae, immunoreactive pattern for myelin basic proteins (MBP) and Golgi impregnated images of oligodendrocytes, with special reference to the influence of aging. All of the hybrid mice had an intermediate coat color between the white of the shiverer and black-brown of the mld, and revealed the same neurological symptoms, intention tremor, ataxic behavior, etc., as those of the shiverer and mld. The central myelin lamellae of the 'shiverer*mld' mouse exhibited the similar characteristics to the shiverer type rather than the mld type from the standpoint of the infrequent occurrence of major dense lines, although they did display a tendency to increase major dense lines with aging like the mld. Observation of the immunohistochemical preparations for MBP showed that immunopositive myelin sheaths were present in the white matter, although they were far more infrequent than those of the mld mutant, probably reflecting the amount of major dense lines. Thus, in the CNS of the 'shiverer*mld' mouse, the MBP-synthesis was possibly much more disturbed than in the mld mutant, or at least, revealed an intermediate pattern between the mld and shiverer. © 1988.

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Myelin proteolipid protein gene structure and its regulation of expression in normal and jimpy mutant mice

Ikenaka Kazuhiro, Furuichi Teiichi, Iwasaki Yasuno, Moriguchi Akira, Okano Hideyuki, Mikoshiba Katsuhiko

Journal of Molecular Biology 199 （ 4 ） 587 - 596 1988年02月

ISSN 0022-2836

The mouse proteolipid protein (PLP) gene was cloned into the λ bacteriophage Charon 4A. The organization and the nucleotide sequence of the exons of the mouse PLP gene were quite similar to those of their human counterparts, consisting of seven exons. The transcription of the PLP gene started from multiple sites. There was a unique sequence tandemly repeated four times, sharing homology with the herpes simplex virus DR2 sequence, upstream from the transcribed region. Expression of the myelin basic protein (MBP) is also restricted to the oligodendrocytes in the central nervous system as is the PLP expression. Homology search against the mouse MBP gene revealed that several boxes in the 5′-flanking region of PLP show a high degree of homology with the sequence present in the MBP 5′-flanking region, possibly of importance in the concomitant expression of both genes in the central nervous system. PLP-mRNA in jimpy mutant mice does not contain exon 5 and its content is greatly reduced. We analyzed the jimpy PLP-mRNA and showed that the transcription initiated from the same sites as those in normal mice. Cloning and sequencing of the 5′-flanking region of the jimpy PLP gene revealed that there were no mutations in the promoter region of the jimpy PLP gene. Therefore, it is likely that a mutation, presumably existing within the jimpy PLP gene, caused the skipping of exon 5 and directly affected the mRNA level. © 1987.

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Gene organization and transcription of duplicated MBP genes of myelin deficient (shi(mld)) mutant mouse.

Okano H., Tamura T., Miura M., Aoyama A., Ikenaka K., Oshimura M., Mikoshiba K.

EMBO Journal 7 （ 1 ） 77 - 83 1988年01月

ISSN 0261-4189

A hereditary dysmyelinating mutation, named myelin deficient (shi(mld)), is characterized by reduced expression of myelin basic protein (MBP). In shi(mld), the MBP gene is duplicated and its reduced expression is mainly determined by the level of mRNA. We have characterized the structure and function of the promoter regions of the duplicated MBP genes in shi(mld). Among the lambda clones containing promoter regions of the duplicated MBP genes in shi(mld), one (gene 1) had the same restriction enzyme pattern as that in control mice, but another (gene 2) had a rearrangement on a distal part of the promoter. A 712-bp nucleotide sequence upstream of the first exons of both of the duplicated MBP genes of shi(mld) was completely consistent with that of the control. Promoter activities of 1.3-kb 5'-flanking regions from respective genes of shi(mld) measured by in vitro run-off assay using HeLa whole-cell extracts were indistinguishable from that of the control MPB gene. Chromosomal mapping by in situ hybridization suggested that the duplicated MBP genes were located closely to each other at the distal part of chromosome 18. A recombinational event including the inversion seemed to have occurred within gene 1 and its possible relationship to the reduced expression of MBP is discussed.

Tissue-specific in vitro transcription from the mouse myelin basic protein promoter

Tamura T. A., Aoyama A., Inoue T., Miura M., Okano H., Mikoshiba K.

Molecular and Cellular Biology 9 （ 7 ） 3122 - 3126 1989年

ISSN 0270-7306

Chimeric and molecular genetic analysis of myelin-deficiency (shiverer and mld) mutant mice

Mikoshiba K., Okano H., Aruga J., Tamura T. A., Miura M., Ikenaka K., Nakagawa T.

Annals of the New York Academy of Sciences 605 166 - 182 1990年

ISSN 0077-8923

The shiverer and myelin-deficient (mld) mutants are two allelic mutations. Both are characterized by hypomyelination in the CNS and deficient expression of the MBP gene. Chimeric analysis of the pathogenesis of shiverer showed that shiverer mutation acts intrinsic to the oligodendrocyte, which is the only cell type expressing. The MBP gene in the CNS. Molecular genetic studies by several groups demonstrated that shiverer is a deletion mutation in the MBP gene. Consequently, no MBP is produced in the shiverer mutant. In mld, however, partial expression of the MBP gene was observed. Interestingly, MBP was expressed in a mosaic fashion in the CNS of mld mice. Molecular genetic studies revealed that the mld mutant has duplicated MBP genes in tandem on a distal part (E2-4) of chromosome 18q. The reduced expression was based on the level of mRNA. A large portion is inverted in the upstream copy, and an intact copy is located downstream. We showed in mld mutants that antisense RNA corresponding to the inverted segment is transcribed, and it forms RNA duplex, with the RNA transcribed from the normal gene located downstream.

Differential localization of alternative spliced transcripts encoding inositol 1,4,5-trisphosphate receptors in mouse cerebellum and hippocampus

Nakagawa Toshiyuki, Shiota Chiyo, Okano Hideyuki, Mikoshiba Katsuhiko

Journal of Neurochemistry 57 （ 5 ） 1807 - 1810 1991年11月

ISSN 0022-3042

Expression of inositol 1,4,5-trisphosphate (InsP₃) receptor subtypes was determined in mouse brain using oligonucleotide-specific in situ hybridization. All subtypes, except one that deletes 120 bp from the full-length InsP₃ receptor cDNA, were expressed in cerebellar Purkinje cells. In hippocampus, various subtypes showed distinct expression patterns. These results suggest that regionally selective expression of InsP₃ receptor subtypes may result in the generation of functionally distinct channels.

Dysmyelination in transgenic mice resulting from expression of class I histocompatibility molecules in oligodendrocytes

Turnley Ann M., Morahan Grant, Okano Hideyuki, Bernard Ora, Mikoshiba Katsuhiko, Allison Janette, Bartlett Perry F., Miller J. F A P

Nature 353 （ 6344 ） 566 - 569 1991年10月

ISSN 0028-0836

MAJOR histocompatibility complex (MHC) molecules are not normally expressed in the central nervous system (CNS)^1-3. However, aberrant expression has been observed in multiple sclerosis lesions and could contribute to the destruction of myelin or the myelinating cells known as oligodendrocytes^4,5. The mechanism of cell damage associated with aberrant MHC molecule expression is unclear: for example, overexpression of class I (ref. 6) and class II (refs 7, 8) MHC molecules in pancreatic β cells in transgenic mice leads to nonimmune destruction of the cells and insulin-dependent diabetes mellitus. We have generated transgenic mice that express class I H-2K^b MHC molecules, under the control of the myelin basic protein promoter, specifically in oligodendrocytes. Homozygous transgenic mice have a shivering phenotype, develop tonic seizures and die at 15-22 days. This phenotype, which we term 'wonky', is due to hypomyelination in the CNS, and not to involvement of the immune system. The primary defect appears to be a shortage of myelinating oligodendrocytes resulting from overexpression of the class I MHC molecules.

The subtypes of the mouse inositol 1,4,5-trisphosphate receptor are expressed in a tissue-specific and developmentally specific manner

Nakagawa Toshiyuki, Okano Hideyuki, Furuichi Teiichi, Aruga Jun, Mikoshiba Katsuhiko

Proceedings of the National Academy of Sciences of the United States of America 88 （ 14 ） 6244 - 6248 1991年07月

ISSN 0027-8424

Additional subtypes of the inositol 1,4,5-trisphosphate (InsP₃) receptor are expressed in a tissue-specific and developmentally specific manner. They differ from the InsP₃ receptor structure previously reported in two small variably spliced segments. One segment (SI) is located within the InsP₃ binding site, whereas another segment (SII) is located near putative sites for phosphorylation and ATP binding to modulate InsP₃ action on Ca²⁺ flux. Therefore, we speculate that selective use of InsP₃ receptor subtypes permits a tissue-specific and developmentally specific expression of functionally distinct channels.

Structure and function of myelin protein genes

Mikoshiba Katsuhiko, Okano Hideyuki, Tamura Taka Aki, Ikenaka Kazuhiro

Annual Review of Neuroscience 14 201 - 217 1991年

ISSN 0147-006X

Identification of the new isoforms of mouse myelin basic protein

Aruga J., Okano H., Mikoshiba K.

Journal of Neurochemistry 56 （ 4 ） 1222 - 1226 1991年

ISSN 0022-3042

Myelin basic protein (MBP) is a major constituent in the myelin of the CNS. In mice, five forms of MBPs (14 kDa, two types of 17 kDa, 18.5 kDa, and 21.5 kDa) encoded by separate mRNAs have been identified based on cDNA cloning studies. These mRNAs are considered to be produced by alternative splicing from a single gene composed of seven exons. Here we report the existence of two novel MBP mRNAs encoding 19.7-kDa and 21-kDa MBPs identified by cDNA cloning using the polymerase chain reaction. Both of these MBPs contain a sequence of a previously unidentified exon of 66 nucleotides, which was mapped to be just 5′ of exon 5 in the MBP gene. MBP mRNAs containing this novel exon (exon 5a) belong to a minor population in the whole brain and PNS and are somewhat enriched in the spinal cord. Exon 5a encodes a very hydrophobic segment rich in valine residues, which presumably forms a β-pleated sheet.

Molecular biology of myelin basic protein

Katsuhiko Mikoshiba, Jun Aruga, Hideyuki Okano

Comparative Biochemistry and Physiology. Part C, Comparative 98 （ 1 ） 51 - 61 1991年

ISSN 0306-4492

1. Myelin is an important structure for facilitating the conduction of impulses along the axons both in the central nervous system (CNS) and peripheral nervous system (PNS). 2. Myelin basic protein (MBP) is a major protein in CNS myelin. 3. MBP is expressed specifically in the nervous system. 4. The MBP gene has been cloned and characterized. 5. Two mutant mice, Shiverer (shi) and myelin-deficient (mld, shi^mid), are autosomal recessive mutants that show severe symptoms such as intentional tremor. They have been found to have a mutation in the MBP gene that results in poor myelination in the central nervous system. 6. It was found that rearrangement within the MBP gene results in low expression of the gene. 7. In Shiverer, the MBP gene is partially deleted (from exons 3 to 7), and in mld, the gene is duplicated tandemly and a large portion of the duplication is inverted upstream of the intact copy. 8. In mld, anti-sense RNA complementary to exons 3-7, which correspond to the inverted segment, was detected by RNase protection studies, and presumed to be responsible for the reduced expressions of MBP. 9.The mechanism of gene rearrangement in MBP was also characterized. 10. This article reviews the recent progress in the study of the MBP gene, especially the rearrangement of the gene and its expression in mutant mice. © 1991.

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Myelin basic protein gene and the function of antisense RNA in its repression in myelin-deficient mutant mouse

Okano Hideyuki, Aruga Jun, Nakagawa Toshiyuki, Shiota Chiyo, Mikoshiba Katsuhiko

Journal of Neurochemistry 56 （ 2 ） 560 - 567 1991年

ISSN 0022-3042

The myelin-deficient (mld) mouse is an autosomal recessive mutant characterized by hypomyelination of the CNS due to reduced expression of the myelin basic protein (MBP) gene. In the mld mutant, the MBP gene is duplicated in tandem. One gene is intact, but a large portion is inverted upstream of the other copy, and its transcription yields the antisense RNA. This antisense RNA was shown to be localized in the nucleus and to form an RNA:RNA duplex with sense RNA. These findings suggested that inhibition of transport from the nucleus or selective degradation of the duplex is responsible for the reduced expression of the MBP gene in the mld mutant. The mechanism of gene rearrangement at the MBP locus was also characterized. Cosmid clones encompassing whole MBP gene loci from control and mld genomic DNA libraries were isolated. The recombination points indicated that the duplication and inversion observed in mld occurred due to nonhomologous recombination.

Recent advances in studies on genes for myelin proteins

Ikenaka K., Okano H., Tamura T. A., Mikoshiba K.

Development Growth and Differentiation 33 （ 3 ） 181 - 192 1991年

ISSN 0012-1592

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