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The Journal of Neuroscience, February 15, 1999, 19(4):1393-1397
Stimulation of Myelin Basic Protein Gene Transcription by Fyn
Tyrosine Kinase for Myelination
Hisashi
Umemori1,
Yasunori
Kadowaki1,
Kazushige
Hirosawa2,
Yutaka
Yoshida1,
Katsunori
Hironaka1,
Hideyuki
Okano3, and
Tadashi
Yamamoto1
Departments of 1 Oncology and 2 Fine
Morphology, Institute of Medical Science, The University of Tokyo,
Minato-ku, Tokyo 108-8639, Japan, and 3 Department of
Neuroanatomy, Biomedical Research Center, Osaka University Medical
School, Core Research for Evolutional Science and Technology (CREST),
and Japan Science and Technology Corporation (JST), Suita-shi, Osaka
565-0871, Japan
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ABSTRACT |
Myelin is synthesized about the time of birth. The Src-family
tyrosine kinase Fyn is involved in the initial events of myelination. Fyn is present in myelin-forming cells and is activated through stimulation of cell surface receptors such as large myelin-associated glycoprotein (L-MAG). Here we show that Fyn stimulates transcription of
the myelin basic protein (MBP) gene for myelination. MBP is a major
component of the myelin membrane. In 4-week-old Fyn-deficient mice, MBP
is significantly reduced, and electron microscopic analysis showed that
myelination is delayed, compared with wild-type mice. The Fyn-deficient
mice had thinner, more irregular myelin than the wild-type. We found
that Fyn stimulates the promoter activity of the MBP gene by
approximately sevenfold. The region responsible for the transactivation
by Fyn is located between nucleotides  675 and 647
with respect to the transcription start site. Proteins binding to this
region were found by gel shift study, and the binding activity
correlates with Fyn activity during myelination. These results suggest
that transactivation of the MBP gene by Fyn is important for myelination.
Key words:
myelination; Fyn tyrosine kinase; myelin basic protein; transactivation; developmental regulation; knock-out mouse
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INTRODUCTION |
Myelin is the lipoprotein
multimembrane that functions as an insulator preventing the flow of ion
currents across the axonal membrane and facilitating the conduction of
electrical nerve impulses. During brain development, myelin formation
is one of the major events in maturation. It is synthesized by
oligodendrocytes in the CNS soon after birth in mammals. For
myelination, oligodendrocytes extend processes to recognize neuronal
axons by cell surface receptors. The receptors generate intracellular
signals in the oligodendrocytes, which enables them to wrap around the
axon to form myelin. Thus, determining the signaling pathway in the
oligodendrocytes is crucial to understanding the mechanism of
myelination. We have shown that initial events of myelination involve
Fyn protein tyrosine kinase (PTK) signaling (Umemori et al., 1994 ).
Fyn, a member of the Src-family nonreceptor PTKs, is activated during
the initial stages of myelination through stimulation of the large
myelin-associated glycoprotein (L-MAG), an adhesion molecule that has
been implicated in myelinogenesis.
Myelin is composed of a limited number of myelin proteins: proteolipid
protein (PLP), myelin basic protein (MBP), 2', 3'-cyclic nucleotide
3'-phosphohydrolase (CNPase), MAG, and several enzymes. Among them, MBP
constitutes 30% of all myelin protein in the CNS. MBP, a functionally
important structural protein of myelin, is localized at opposing
cytoplasmic faces of the myelin lamellae, which form the major dense
line in electron micrographs (Lemke, 1988). Five different forms of
MBPs with molecular masses of 14-21.5 kDa are produced by alternative
use of seven exons in mouse brain (for review, see Mikoshiba et al.,
1991). In the CNS, MBP gene expression is differentially regulated
during myelinogenesis (Okano et al., 1987). Cell- and stage-specific
regulation of MBP gene expression in brain is regulated at the
transcriptional level (Kamholz et al., 1988; Shiota et al., 1991). The
5'-flanking region of the MBP gene contains several regulatory elements
that differentially contribute to the cell type-specific transcription
(Miura et al., 1989; Tamura et al., 1989; Devine-Beach et al., 1990;
Asipu and Blair, 1994). In addition, several MBP promoter-binding
proteins have been identified (Inoue et al., 1990; Haque et al., 1994; Haas et al., 1995). However, biological signals from cell surface receptors that activate MBP gene transcription during myelination remain to be elucidated.
Here we show that signals through Fyn PTK stimulate transcription of
the MBP gene. Fyn serves as a signaling molecule from cell surface
receptors, such as MAG, to the nucleus to transactivate the MBP gene in
the initial stages of myelination. The present study with Fyn-deficient
mice shows that this signaling is important for myelin formation.
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MATERIALS AND METHODS |
Lysate preparation. Brains and spinal cords were
removed from wild-type and Fyn-deficient mice and lysed in
Tris-NP40-EDTA (TNE) buffer (Umemori et al., 1994), and equal
amounts of lysates were subjected to immunoblotting.
Immunoblotting. Equal amounts of lysates (20 µg protein)
were separated on 15% SDS-PAGE and transferred to polyvinylidene difluoride membranes. After blocking, the filters were probed with
anti-MBP antibody (Nichirei, Tokyo, Japan) followed by treatment with
125I-labeled protein A (ICN, Costa Mesa, CA). The amount of
MBP was measured using a Fujix Bio Image Analyzer, BAS 2000.
Plasmid construction. The deletions of the MBP promoter used
in Figure 3 were described previously (Miura et al., 1989). These deletions were subcloned into pUC00 chloramphenicol acetyltransferase (CAT) (Uchiumi et al., 1992). Deletions used in Figure 4 were constructed by site-directed mutagenesis (Kunkel, 1985). A
BamHI site was introduced at the position of bp 692,
675, 656, or 647 of pBG1b, and the more distal region was
removed by digestion with BamHI. The deletion in Figure 5
was constructed by PCR. The PCR product with primers
5'-GACCAAAGCTTATTCCTCACC-3' and 5'-GGCACTGCAGAATCC-CTCTCC-3' was
subcloned into the HindIII-PstI site of pBG1b.
Sense and antisense oligonucleotides for the Fyn response sequence with
HindIII sites at both ends were synthesized, annealed, and
cloned into TK-CAT (see Fig. 6) (Kadowaki et al., 1995). All
constructs were confirmed by sequencing. The construction of the
expression plasmid for the constitutively active form of Fyn has been
described previously (Takeuchi et al., 1993).
Chloramphenicol acetyltransferase assay. CV1 cells
were transfected with 5 µg of each MBP promoter-CAT plasmid
and 5 µg of pME18S vector (Takebe et al., 1988) or Fyn expression
plasmid by the calcium phosphate precipitation method. After 48 hr
incubation, the cell extracts were prepared as described previously
(Kadowaki et al., 1995), and protein concentrations were normalized.
CAT assay was performed as described previously (Umesono et al., 1988). CAT activities were quantified by a Fujix Bio Image Analyzer, BAS 2000.
Gel shift assay. The gel shift assay was performed as
described previously (Kadowaki et al., 1992). Briefly, 5 µg of
nuclear extract from CV1 cells or brains in a binding buffer was
incubated at 4°C for 20 min. Unlabeled competitors were added at this
time. Then, 30 fmol of [32P]-labeled Fyn response
sequence probe (1 × 105 cpm) was added, and
the reaction mixture was incubated again for 30 min at room
temperature. The bound complex was then resolved by 5% PAGE.
Electron microscopic analysis. Spinal cords were removed
from 4-week-old Fyn-deficient and wild-type mice and processed for electron microscopy. Electron microscopic analysis was performed as
described previously (Yoon et al., 1996).
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RESULTS |
Electron microscopic analysis of myelin in Fyn-deficient mice
Because Fyn is activated through L-MAG in the initial stages of
myelination (Umemori et al., 1994), we searched for target genes
downstream of the Fyn-mediated signaling pathway. Because the amount of
myelin in 4-week-old Fyn-deficient mice (Yagi et al., 1993) is
~50-60% of that in wild-type mice (Umemori et al., 1994), we first
examined the structure of myelin in 4-week-old Fyn-deficient and
wild-type mice by electron microscopy. As shown in Figure
1, myelin in Fyn-deficient mice was
thinner than that in wild-type mice. Quantitative analysis showed that
myelin thickness in Fyn-deficient mice was ~70% of that in wild-type
mice. In addition, myelin in Fyn-deficient mice was irregular in form
relative to that in wild-type mice. These observations suggest that
myelin in 4-week-old Fyn-deficient mice is immature. When we examined myelin in 12-week old mice, no obvious difference was detected between
Fyn-deficient and wild-type mice (data not shown). Therefore, we
conclude that myelination is delayed in Fyn-deficient mice.
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Figure 1.
Electron microscopic analysis of myelin in
4-week-old Fyn-deficient and wild-type mice. Typical electron
micrographs of spinal cord sections of 4-week-old Fyn-deficient
(Fyn /) and wild-type mice are shown. Scale bars,
1 µm. 5000× magnification.
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Amount of MBP is reduced in Fyn-deficient mice
On the basis of the result from electron microscopic analysis, we
assumed that the expression of structural proteins of myelin might be a
target of Fyn signaling. In wild-type mice, MBP expression is increased
during postnatal days 4-12, which is just after Fyn activation
(Umemori et al., 1994). To examine whether MBP expression is a
downstream event of Fyn signaling, we measured the amount of MBP in
4-week-old mice. Equal amounts of brain or spinal cord lysates obtained
from wild-type and Fyn-deficient mice were subjected to immunoblotting
with anti-MBP antibody. As shown in Figure
2, the amount of MBP was significantly
decreased in Fyn-deficient mice compared with that in wild-type mice
(56.7% of wild-type in Fyn-deficient brain and 31.9% in spinal
cord).
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Figure 2.
Amount of MBP in wild-type and Fyn-deficient mice.
Equal amounts of brain or spinal cord lysates obtained from 4-week-old
wild-type and Fyn-deficient mice were subjected to immunoblotting with
anti-MBP. The amounts of MBP were determined by densitometric scanning
of the corresponding bands. Results are presented as densitometric
units normalized to the value for the wild type. Error bars represent
SEM (n = 6).
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Transcriptional activation of the MBP gene by Fyn
To determine the mechanism of the MBP expression through Fyn
signaling, we examined the effect of Fyn on MBP gene transcription. We
fused the 1318 bp 5'-flanking sequence of the MBP gene (Miura et al.,
1989) to the CAT reporter gene. This construct was transfected into CV1
cells, and the CAT activity was measured in the presence or absence of
a constitutively active form of Fyn (Takeuchi et al., 1993). As shown
in Figure 3 (pBG1b), Fyn stimulated
promoter activity of the MBP gene by approximately sevenfold.
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Figure 3.
Activation of the MBP gene transcription by Fyn.
Deletion constructs of the MBP promoter-CAT and the transactivation by
Fyn (fold activation) are shown. The indicated base pair is from the
transcription start site. CV1 cells were transfected with each MBP
promoter-CAT plasmid and pME18S vector or Fyn expression plasmid.
Enzyme activities in the presence of Fyn were normalized against the
activities with pME18S vector. The results are expressed as means ± SD of five separate experiments.
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Identification of Fyn response sequence in the MBP promoter
To identify the critical regions responsible for Fyn-mediated
transactivation of the MBP gene, we used a series of deletions in the
MBP promoter as shown in Figure 3 (Miura et al., 1989). The
transactivation effect of Fyn on the MBP promoter disappeared when the
promoter sequence was eliminated up to bp -396 (pBG1d). Therefore, the
Fyn response region is located between bp -714 and -396 with respect
to the transcription start site.
To further narrow the Fyn response sequence on the MBP promoter, we
constructed another series of more minute deletions between bp -714
and -396. As shown in Figure 4, Fyn
stimulated the deletion of up to bp -675. However, the promoter with
deletion of up to bp -656 was not transactivated by Fyn. Thus,
Fyn-induced activation of the MBP promoter requires the sequence
between bp -675 and -656.
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Figure 4.
Identification of the sequence required for
Fyn-dependent transactivation of the MBP promoter. The deletion
constructs of the MBP promoter contain positions indicated on the
top line. Enzyme activities in the presence of Fyn were
normalized against the activities with pME18S vector (fold activation).
The results are expressed as means ± SD of three separate
experiments. The sequence used for the experiments depicted in Figures
6 and 7 is shown at the top.
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To prove that this is the only Fyn response sequence, we constructed a
mutant promoter with deletion between bp -687 and -656 (Fig.
5,
pB 687-656). This deleted promoter was
not transactivated by Fyn (Fig. 5). Therefore, the sequence between bp
-687 and -656 is essential for transactivation of the MBP promoter by
Fyn, suggesting that this region is the only sequence responsive
to Fyn in the MBP promoter.
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Figure 5.
Deletion of the MBP promoter between 687 and
-656 eliminates transactivation by Fyn. The deletion constructs of the
MBP promoter contain positions indicated on the top
line. Enzyme activities in the presence of Fyn were normalized
against the activities with pME18S vector (fold activation). The
results are expressed as means ± SD of three separate
experiments.
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To show that the sequence above is sufficient for activation by Fyn, we
fused the sequence between bp -675 and -647 with CAT reporter gene
containing thymidine kinase promoter (Fig.
6A); we then
transfected the construct with Fyn expression plasmid into CV1 cells.
The CAT assay revealed that the sequence between bp -675 and -647 was
sufficient for transactivation by Fyn (approximately four- to
fivefold) (Fig. 6B). Thus, we conclude that
the sequence between bp -675 and -647 of the MBP promoter includes
the Fyn response sequence.
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Figure 6.
The sequence between bp -675 and -647 of the MBP
promoter is responsible for Fyn-dependent transactivation. The sequence
between bp -675 and -647 of the MBP promoter was fused to the CAT
reporter gene with TK promoter (A,
TK-FRS-CAT) and transfected with pME18S vector
() or Fyn expression plasmid (+) into CV1 cells. Results of the CAT
assay are shown as fold activation by Fyn (B).
Means ± SD.
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Binding of nuclear proteins to the Fyn response sequence is
developmentally regulated
We next examined whether nuclear proteins can interact with the
sequence required for Fyn-dependent transactivation. As a gel shift
probe, we prepared a synthetic oligonucleotide corresponding to the
sequence between bp -675 and -647 (Fig. 4). Nuclear extracts were
prepared from CV1 cells and subjected to the gel shift assay. As shown
in Figure 7A, proteins
interacting with the Fyn response sequence were found in the nuclear
extracts prepared from CV1 cells. The competition assays using specific
and nonspecific oligonucleotide competitors suggested that the complex
formation was sequence specific.
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Figure 7.
Developmental regulation of protein binding to the
Fyn response element. A, Nuclear extracts were prepared
from CV1 cells and incubated with end-labeled Fyn response element ()
in the presence of unlabeled specific (S) or
nonspecific (N) competitors. The
arrow indicates a band specific for the Fyn response
element. B, Nuclear extracts were prepared from brains
of 4-d-old (P4) and 30-d-old (P30)
mice and incubated with Fyn response element. The arrow
indicates a developmentally regulated band specific for the Fyn
response element.
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We then examined whether the complex formation is developmentally
regulated. For this, we prepared nuclear extracts from the brains of 4- and 30-d-old mice and subjected them to the gel shift assay. As shown
in Figure 7B, strong interaction of the Fyn response sequence with binding proteins was detected with the P4 extract, whereas much weaker interaction was observed with the P30 extract. Therefore, the complex formation is regulated developmentally, which
correlates with Fyn kinase activity (Umemori et al., 1994). From these
results, we conclude that the sequence between bp -675 and -647 of
the MBP promoter includes the Fyn response element with which
transcription factors stimulated by Fyn interact during myelination.
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DISCUSSION |
This study shows that Fyn stimulates MBP gene transcription for
myelination. Despite recent progress in the identification and
characterization of genes encoding myelin components, the molecular
mechanisms controlling the process of myelination have remained
elusive. Here we have demonstrated a signaling pathway from the cell
surface to a gene expression that is important in the early phase of
myelination. The putative signaling pathway is schematically
illustrated in Figure 8. The signal from
neuron-oligodendrocyte interaction activates Fyn PTK. Fyn
phosphorylates its substrates and may stimulate transcription factors.
Consequently, MBP gene transcription is stimulated, and the amount of
MBP increases, which is necessary for myelin formation. The study with
Fyn-deficient mice supports the importance of this signaling pathway
for myelination.
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Figure 8.
Schematic illustration for the role of the
signaling through Fyn PTK in myelination. The signal from
neuron-oligodendrocyte interaction (such as from L-MAG)
activates Fyn PTK. Fyn phosphorylates its substrates and stimulates
transcription factors. Thus, MBP gene transcription is stimulated and
the amount of MBP increases, which is necessary for forming myelin. The
Fyn response element and the positions of the interferon- response
element core sequence (-IRE CS) and NF-IL6 core
sequence (NF-IL6 CS) are indicated with their consensus
sequences. Single letter code: W = A
or T, K = G or
T, Y = C or
T, N = A or
G or C or T.
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Search for previously known consensus transcription factor response
elements revealed that the Fyn response region contains the
interferon- responsive element core sequence and the NF-IL6 core
sequence (NF-IL6 CS) (Fig. 8). Interferon- signaling involves Janus
kinase (JAK) family PTKs (Ihle et al., 1994). Therefore Fyn and
JAK family PTKs may share downstream signals. Indeed, both PTK families
are known to activate the signal transducers and activators of
transcription family of transcription factors (Cao et al.,
1996). NF-IL6 belongs to the CCAAT/enhancer binding protein
(C/EBP) family of transcription factors, the activity of which
is regulated by phosphorylation by several kinases including MAP kinase
(Nakajima et al., 1993) and PKC (Mahoney et al., 1992). Fyn may
directly phosphorylate C/EBP transcription factors or may regulate them
through MAP kinase or PKC. In addition, C/EBP family transcription
factor is known to interact with NF B (Stein et al., 1993). We have
shown previously that Fyn can activate NFB-like proteins (Houhashi
et al., 1995). Thus, C/EBP-NFB interaction may be regulated by Fyn
PTK. Myelination signaling through Fyn might stimulate such
transcription factors.
Because the cell type-specific transcription of the MBP gene is
regulated by a more proximal region of the MBP promoter than the Fyn
response region (Tamura et al., 1989; Devine-Beach et al., 1990),
signaling through Fyn would not regulate cell specificity but rather
regulates stage-specific transcription as suggested in Figure
7B. Fyn signaling might be required for initiating
myelination. Identification of both cell- and stage-specific
transcription signaling will further clarify the molecular mechanism of
myelination and will be a clue to other biological events in
development and differentiation.
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FOOTNOTES |
Received Aug. 7, 1998; revised Nov. 30, 1998; accepted Nov. 30, 1998.
This work was supported by grants from the Ministry of Education,
Science, Sports, and Culture of Japan. We thank S. Aizawa for providing
Fyn-deficient mice, and M. Miura, K. Mikoshiba, and T. Tanaka for their encouragement.
Correspondence should be addressed to Dr. T. Yamamoto, Department of
Oncology, Institute of Medical Science, The University of Tokyo,
Minato-ku, Tokyo 108-8639, Japan.
Dr. Umemori's present address: Department of Anatomy and Neurobiology,
Washington University School of Medicine, St. Louis, MO 63110.
Dr. Kadowaki's present address: Department of Internal Medicine (1),
Daisan Hospital, The Jikei University School of Medicine, Izumihonchou
Komae City, Tokyo 201, Japan.
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REFERENCES |
-
Asipu A,
Blair GE
(1994)
Regulation of myelin basic protein-encoding gene transcription in rat oligodendrocytes.
Gene
150:227-234[Web of Science][Medline].
-
Cao X,
Tay A,
Guy GR,
Tan YH
(1996)
Activation and association of Stat3 with Src in v-Src-transformed cell lines.
Mol Cell Biol
16:1595-1603[Abstract].
-
Devine-Beach K,
Lashgari MS,
Khalili K
(1990)
Myelin basic protein gene transcription. Identification of proximal and distal cis-acting regulatory elements.
J Biol Chem
265:13830-13835[Abstract/Free Full Text].
-
Haas S,
Thatikunta P,
Steplewski A,
Johnson EM,
Khalili K,
Amini S
(1995)
A 39-kD DNA-binding protein from mouse brain stimulates transcription of myelin basic protein gene in oligodendrocytic cells.
J Cell Biol
130:1171-1179[Abstract/Free Full Text].
-
Haque NS,
Buchberg AM,
Khalili K
(1994)
Isolation and characterization of MRF-1, a brain-derived DNA-binding protein with a capacity to regulate expression of myelin basic protein gene.
J Biol Chem
269:31149-31156[Abstract/Free Full Text].
-
Houhashi N,
Hayashi T,
Fusaki N,
Takeuchi M,
Higurashi M,
Okamoto T,
Semba K,
Yamamoto T
(1995)
The protein tyrosine kinase Fyn activates transcription from the HIV promoter via activation of NFB-like DNA-binding proteins.
Int Immunol
7:1851-1859[Abstract/Free Full Text].
-
Ihle JN,
Witthuhn BA,
Quelle FW,
Yamamoto K,
Thierfelder WE,
Kreider B,
Silvennoinen O
(1994)
Signaling by the cytokine receptor superfamily: JAKs and STATs.
Trends Biochem Sci
19:222-227[Web of Science][Medline].
-
Inoue T,
Tamura T,
Furuichi T,
Mikoshiba K
(1990)
Isolation of complementary DNAs encoding a cerebellum-enriched nuclear factor I family that activates transcription from the mouse myelin basic protein promoter.
J Biol Chem
265:19065-19070[Abstract/Free Full Text].
-
Kadowaki Y,
Toyoshima K,
Yamamoto T
(1992)
Ear3/COUP-TF binds most tightly to a response element with tandem repeat separated by one nucleotide.
Biochem Biophys Res Commun
183:492-498[Web of Science][Medline].
-
Kadowaki Y,
Toyoshima K,
Yamamoto T
(1995)
Dual transcriptional control by Ear3/COUP: negative regulation through the DR1 direct repeat and positive regulation through a sequence downstream of the transcriptional start site of the mouse mammary tumor virus promoter.
Proc Natl Acad Sci USA
92:4432-4436[Abstract/Free Full Text].
-
Kamholz J,
Toffenetti J,
Lazzarini RA
(1988)
Organization and expression of the human myelin basic protein gene.
J Neurosci Res
21:62-70[Web of Science][Medline].
-
Kunkel TA
(1985)
Rapid and efficient site-specific mutagenesis without phenotypic selection.
Proc Natl Acad Sci USA
82:488-492[Abstract/Free Full Text].
-
Lemke G
(1988)
Unwrapping the genes of myelin.
Neuron
1:535-543[Web of Science][Medline].
-
Mahoney CW,
Shuman J,
McKnight SL,
Chen H-C,
Huang K-P
(1992)
Phosphorylation of CCAAT-enhancer binding protein by protein kinase C attenuates site-selective DNA binding.
J Biol Chem
267:19396-19403[Abstract/Free Full Text].
-
Mikoshiba K,
Okano H,
Tamura T,
Ikenaka K
(1991)
Structure and function of myelin protein genes.
Annu Rev Neurosci
14:201-217[Web of Science][Medline].
-
Miura M,
Tamura T,
Aoyama A,
Mikoshiba K
(1989)
The promoter elements of the mouse myelin basic protein gene function efficiently in NG108-15 neuronal/glial cells.
Gene
75:31-38[Web of Science][Medline].
-
Nakajima T,
Kinoshita S,
Sasagawa T,
Sasaki K,
Naruto M,
Kishimoto T,
Akira S
(1993)
Phosphorylation at threonine-235 by a ras-dependent mitogen-activated protein kinase cascade is essential for transcription factor NF-IL6.
Proc Natl Acad Sci USA
90:2207-2211[Abstract/Free Full Text].
-
Okano H,
Miura M,
Moriguchi A,
Ikenaka K,
Tsukada Y,
Mikoshiba K
(1987)
Inefficient transcription of the myelin basic protein gene possibly causes hypomyelination in myelin deficient mutant mice.
J Neurochem
48:470-477[Web of Science][Medline].
-
Shiota C,
Ikenaka K,
Mikoshiba K
(1991)
Developmental expression of myelin protein genes in dysmyelinating mutant mice: analysis by nuclear run-off transcription assay, in situ hybridization, and immunohistochemistry.
J Neurochem
56:818-826[Web of Science][Medline].
-
Stein B,
Cogswell PC,
Baldwin Jr AS
(1993)
Functional and physical associations between NF-B and C/EBP family members: a Rel domain-bZIP interaction.
Mol Cell Biol
13:3964-3974[Abstract/Free Full Text].
-
Takebe Y,
Seiki M,
Fujisawa J,
Hoy P,
Yokota K,
Arai K,
Yoshida M,
Arai N
(1988)
SR
 promoter: an efficient and versatile mammalian cDNA expression system composed of the simian virus 40 early promoter and the R-U5 segment of human T-cell leukemia virus type 1 long terminal repeat.
Mol Cell Biol
8:466-472[Abstract/Free Full Text]. -
Takeuchi M,
Kuramochi S,
Fusaki N,
Nada S,
Kawamura-Tsuzuku J,
Matsuda S,
Semba K,
Toyoshima K,
Okada M,
Yamamoto T
(1993)
Functional and physical interaction of protein-tyrosine kinases Fyn and Csk in the T-cell signaling system.
J Biol Chem
268:27413-27419[Abstract/Free Full Text].
-
Tamura T,
Aoyama A,
Inoue T,
Miura M,
Okano H,
Mikoshiba K
(1989)
Tissue-specific in vitro transcription from the mouse myelin basic protein promoter.
Mol Cell Biol
9:3122-3126[Abstract/Free Full Text].
-
Uchiumi F,
Semba K,
Yamanashi Y,
Fujisawa J,
Yoshida M,
Inoue K,
Toyoshima K,
Yamamoto T
(1992)
Characterization of the promoter region of the src family gene lyn and its transactivation by human T-cell leukemia virus type I-encoded p40tax.
Mol Cell Biol
12:3784-3795[Abstract/Free Full Text].
-
Umemori H,
Sato S,
Yagi T,
Aizawa S,
Yamamoto T
(1994)
Initial events of myelination involve Fyn tyrosine kinase signalling.
Nature
367:572-576[Medline].
-
Umesono K,
Giguere V,
Glass SK,
Rosenfeld MG,
Evans RM
(1988)
Retinoic acid and thyroid hormone induce gene expression through a common responsive element.
Nature
336:262-265[Medline].
-
Yagi T,
Aizawa S,
Tokunaga T,
Shigetani Y,
Takeda N,
Ikawa Y
(1993)
A role for Fyn tyrosine kinase in the suckling behaviour of neonatal mice.
Nature
366:742-745[Medline].
-
Yoon C-S,
Hirosawa K,
Suzuki E
(1996)
Studies on the structure of ocellar photoreceptor cells of Drosophila melanogaster with special reference to subrhabdomeric cisternae.
Cell Tissue Res
284:77-85[Web of Science][Medline].
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D. A. Chudakova, Y. H. Zeidan, B. W. Wheeler, J. Yu, S. A. Novgorodov, M. S. Kindy, Y. A. Hannun, and T. I. Gudz
Integrin-associated Lyn Kinase Promotes Cell Survival by Suppressing Acid Sphingomyelinase Activity
J. Biol. Chem.,
October 24, 2008;
283(43):
28806 - 28816.
[Abstract]
[Full Text]
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R. White, C. Gonsior, E.-M. Kramer-Albers, N. Stohr, S. Huttelmaier, and J. Trotter
Activation of oligodendroglial Fyn kinase enhances translation of mRNAs transported in hnRNP A2-dependent RNA granules
J. Cell Biol.,
October 17, 2008;
181(4):
579 - 586.
[Abstract]
[Full Text]
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V. Pernet, S. Joly, F. Christ, L. Dimou, and M. E. Schwab
Nogo-A and Myelin-Associated Glycoprotein Differently Regulate Oligodendrocyte Maturation and Myelin Formation
J. Neurosci.,
July 16, 2008;
28(29):
7435 - 7444.
[Abstract]
[Full Text]
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Y. Miyamoto, J. Yamauchi, J. R. Chan, A. Okada, Y. Tomooka, S.-i. Hisanaga, and A. Tanoue
Cdk5 regulates differentiation of oligodendrocyte precursor cells through the direct phosphorylation of paxillin
J. Cell Sci.,
December 15, 2007;
120(24):
4355 - 4366.
[Abstract]
[Full Text]
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N. Hoshina, T. Tezuka, K. Yokoyama, H. Kozuka-Hata, M. Oyama, and T. Yamamoto
Focal adhesion kinase regulates laminin-induced oligodendroglial process outgrowth.
Genes Cells,
November 1, 2007;
12(11):
1245 - 1254.
[Abstract]
[Full Text]
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S. N. Fewou, H. Ramakrishnan, H. Bussow, V. Gieselmann, and M. Eckhardt
Down-regulation of Polysialic Acid Is Required for Efficient Myelin Formation
J. Biol. Chem.,
June 1, 2007;
282(22):
16700 - 16711.
[Abstract]
[Full Text]
[PDF]
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H. Colognato, J. Galvin, Z. Wang, J. Relucio, T. Nguyen, D. Harrison, P. D. Yurchenco, and C. ffrench-Constant
Identification of dystroglycan as a second laminin receptor in oligodendrocytes, with a role in myelination
Development,
May 1, 2007;
134(9):
1723 - 1736.
[Abstract]
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R. F. Stachlewitz, M. A. Hart, B. Bettencourt, T. Kebede, A. Schwartz, S. E. Ratnofsky, D. J. Calderwood, W. O. Waegell, and G. C. Hirst
A-770041, a Novel and Selective Small-Molecule Inhibitor of Lck, Prevents Heart Allograft Rejection
J. Pharmacol. Exp. Ther.,
October 1, 2005;
315(1):
36 - 41.
[Abstract]
[Full Text]
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S. Li, P. Liquari, K. K. McKee, D. Harrison, R. Patel, S. Lee, and P. D. Yurchenco
Laminin-sulfatide binding initiates basement membrane assembly and enables receptor signaling in Schwann cells and fibroblasts
J. Cell Biol.,
April 11, 2005;
169(1):
179 - 189.
[Abstract]
[Full Text]
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Q.-L. Cui, W.-H. Zheng, R. Quirion, and G. Almazan
Inhibition of Src-like Kinases Reveals Akt-dependent and -independent Pathways in Insulin-like Growth Factor I-mediated Oligodendrocyte Progenitor Survival
J. Biol. Chem.,
March 11, 2005;
280(10):
8918 - 8928.
[Abstract]
[Full Text]
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Z. Lu, L. Ku, Y. Chen, and Y. Feng
Developmental Abnormalities of Myelin Basic Protein Expression in fyn Knock-out Brain Reveal a Role of Fyn in Posttranscriptional Regulation
J. Biol. Chem.,
January 7, 2005;
280(1):
389 - 395.
[Abstract]
[Full Text]
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H. Colognato, S. Ramachandrappa, I. M. Olsen, and C. ffrench-Constant
Integrins direct Src family kinases to regulate distinct phases of oligodendrocyte development
J. Cell Biol.,
October 25, 2004;
167(2):
365 - 375.
[Abstract]
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X. Liang, N. A. Draghi, and M. D. Resh
Signaling from Integrins to Fyn to Rho Family GTPases Regulates Morphologic Differentiation of Oligodendrocytes
J. Neurosci.,
August 11, 2004;
24(32):
7140 - 7149.
[Abstract]
[Full Text]
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B. R. Sperber, E. A. Boyle-Walsh, M. J. Engleka, P. Gadue, A. C. Peterson, P. L. Stein, S. S. Scherer, and F. A. McMorris
A Unique Role for Fyn in CNS Myelination
J. Neurosci.,
March 15, 2001;
21(6):
2039 - 2047.
[Abstract]
[Full Text]
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K. Biffiger, S. Bartsch, D. Montag, A. Aguzzi, M. Schachner, and U. Bartsch
Severe Hypomyelination of the Murine CNS in the Absence of Myelin-Associated Glycoprotein and Fyn Tyrosine Kinase
J. Neurosci.,
October 1, 2000;
20(19):
7430 - 7437.
[Abstract]
[Full Text]
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Z. Li, Y. Zhang, D. Li, and Y. Feng
Destabilization and Mislocalization of Myelin Basic Protein mRNAs in quaking Dysmyelination Lacking the QKI RNA-Binding Proteins
J. Neurosci.,
July 1, 2000;
20(13):
4944 - 4953.
[Abstract]
[Full Text]
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R. Bansal, S. Winkler, and S. Bheddah
Negative Regulation of Oligodendrocyte Differentiation by Galactosphingolipids
J. Neurosci.,
September 15, 1999;
19(18):
7913 - 7924.
[Abstract]
[Full Text]
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Top
Abstract
Introduction
