Developmentally regulated alternative splicing of brain myelin‐associated glycoprotein mRNA is lacking in the quaking mouse

Fujita, Nobuya; Sato, Shuzo; Kurihara, Tadashi; Ishii, Takashi; Takahashi, Yasuo; Miyatake, Tadashi

doi:10.1016/0014-5793(88)80762-2

Cited by 56 publications

(33 citation statements)

References 15 publications

(15 reference statements)

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“…Previous studies indicated that, in comparison to control mice, the mRNA for S-MAG was substantially overexpressed relative to that for L-MAG in quaking brain (Frail et al, 1985;Fujita et al, 1988). However, subsequent reports in which expression of the L-and S-MAG proteins was monitored by Western blotting reached different conclusions.…”

Section: Discussionmentioning

confidence: 95%

“…The level of L-MAG mRNA is dramatically reduced in quaking CNS (Frail et al, 1985;Fujita et al, 1988), while L-MAG has been reported to be either scarcely detectable (Fujita et al, 1990;Bartoszewicz et al, 1994) or present in equal levels to S-MAG (Braun et al, 1990). S-MAG mRNA levels are increased when compared with controls, while the level of S-MAG protein is reduced in quaking, but not to the same degree as L-MAG (Fujita et al, 1990;Fujita et al, 1988;Bartoszewicz et al, 1994). In quaking, the molecular weight of both L-and S-MAG is increased, due to abnormal glycosylation (Matthieu et al, 1974;Bartoszewicz et al, 1994).…”

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confidence: 99%

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Endocytic depletion of L-MAG from CNS myelin in quaking mice.

Bø

Quarles

Fujita

et al. 1995

The Journal of Cell Biology

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Abstract. Quaking is an autosomal recessive hypo/dysmyelinating mutant mouse which has a 1-Mbp deletion on chromosome 17. The mutation exhibits pleiotrophy and does not include genes encoding characterized myelin proteins. The levels of the 67-kD isoform of the myelin-associated glycoprotein (S-MAG) relative to those of the 72-kD isoform (L-MAG) are increased in the quaking CNS, but not in other dysmyelinating mutants. Abnormal expression of MAG isoforms in quaking may result from altered transcription of the MAG gene or from abnormal sorting, transport, or targeting of L-MAG or S-MAG. To test these hypotheses, we have determined the distribution of L-MAG and S-MAG in cervical spinal cord of 7-, 14-, 21-, 28-, and 35-d-old quaking mice. In 7-d-old quaking and control spinal cord, L-and S-MAG was detectable in periaxonal regions of myelinated fibers and in the perinuclear cytoplasm of oligodendrocytes. Between 7 and 35 d, L-MAG was removed from the periaxonal membrane of quaking but not control mice. Compared to control mice, a significant increase in MAG labeling of endosomes occurred within oligodendrocyte cytoplasm of 35-d-old quaking mice. S-MAG remained in periaxonal membranes of both quaking and control mice. Analysis of the cytoplasmic domain of L-MAG identifies amino acid motifs at tyrosine 35 and tyrosine 65 which meet the criteria for "tyrosine internalization signals" that direct transmembrane glycoproteins into the endocytic pathway. These results establish that L-MAG is selectively removed from the periaxonal membrane of CNSmyelinated fibers by receptor-mediated endocytosis. The loss of L-MAG from quaking periaxonal membranes results from increased endocytosis of L-MAG and possibly a decrease in L-MAG production.

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Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 99%

Endocytic depletion of L-MAG from CNS myelin in quaking mice.

Bø

Quarles

Fujita

et al. 1995

The Journal of Cell Biology

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“…Interestingly, some abnormalities in RNA metabolism have been observed in the neural tissue of qk v mutant mice. Proportions of particular alternatively spliced mRNA isoforms of myelin-associated glycoprotein, MAG (Fujita et al 1988;Braun et al 1990;Bartoszewicz et al 1995), and myelin basic protein, MBP (Carnow et al 1984), are altered in qk mice, whereas other mRNAs are unaffected. These observations are consistent with the experimental results indicating that blocking Xqua function prevents the accumulation of Xnot-2, Xbra, and gsc transcripts.…”

Section: The Role Of Quaking In Vertebrate Developmentmentioning

confidence: 99%

The KH domain protein encoded by quaking functions as a dimer and is essential for notochord development inXenopus embryos

Zorn¹,

Krieg²

1997

Genes Dev.

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Mutations in the mouse indicate that quaking gene function is essential for both embryogenesis and for development of the nervous system. Recent isolation of the mouse quaking gene identified a putative RNA-binding protein containing a single KH domain. We have previously isolated the Xenopus homolog of quaking, Xqua, and shown that the sequence is highly conserved through evolution. Here, we report experimental data on the biochemical function of the quaking protein and its role during development. We demonstrate that the quaking protein expressed during early embryogenesis, pXqua 357 , can bind RNA in vitro, and we have mapped the regions of the protein that are essential for RNA binding. We present evidence that pXqua can form homodimers and that dimerization may be required for RNA binding. Oocyte injection experiments show that pXqua 357 is located in both the nucleus and cytoplasm. In the Xenopus embryo, Xqua is first expressed during gastrulation in the organizer region and its derivative, the notochord. In later stage embryos, Xqua is expressed in a number of mesodermal and neural tissues. We demonstrate that disruption of normal Xqua function, by overexpression of a dominant inhibitory form of the protein, blocks notochord differentiation. Xqua function appears to be required for the accumulation of important mRNAs such as Xnot, Xbra, and gsc. These results indicate an essential role for the quaking RNA-binding protein during early vertebrate embryogenesis.

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“…This pattern is similar to the effect of hypothyroidism on microtubule-associated protein-2 in the cerebellum (40). In contrast, normalization in the hippocampus and striatum did not occur before days [25][26][27][28][29][30], and myelination in the cerebral cortex was impaired beyond the first month of life.…”

Section: Resultsmentioning

confidence: 99%

“…MAG is a member of the immunoglobulin superfamily, with strong homologies with cell adhesion molecules such as N-CAM, Ll (Ng-CAM), and Jl (21,25,26). In hypomyelinating mutant mice (quaking), a splicing defect of the MAG gene has been found (27), and direct proof that binding of oligodendrocytes to neurons is mediated by MAG has been obtained (28). From its cell adhesion properties, the early expression of MAG is proposed to play a critical role in myelination, by establishing homotypic interactions among oligodendrocytes, or heterotypic interactions between oligodendrocytes and neurons (25,26 …”

mentioning

confidence: 99%

Neonatal hypothyroidism affects the timely expression of myelin-associated glycoprotein in the rat brain.

Rodrı́guez-Peña

Ibarrola²,

Íñiguez³

et al. 1993

J. Clin. Invest.

159

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Congenital hypothyroidism strongly affects myelination. To assess the role of thyroid hormone on myelin gene expression, we have studied the effect of hypothyroidism on the steady state levels of myelin-associated glycoprotein (MAG) and its mRNA in rat brain during the first postnatal month. As studied by immunoblot analysis of several brain regions, MAG increased from days 10-15 onwards, reaching constant levels by days 20-25. Hypothyroid samples showed a delay in the accumulation of MAG that was more severe in rostral regions, such as cortex and hippocampus. The effect of hypothyroidism on the accumulation of the protein correlated with mRNA levels. MAG mRNA started to accumulate in the cerebrum of normal animals by postnatal day 7, reaching maximal levels by day 20. Hypothyroid rats showed a delay of several days in the onset of mRNA expression, increasing thereafter at the same rate as in normal animals, and eventually reaching similar values. When individual brain regions were analyzed, we found strong regional differences in the effect of hypothyroidism. The cerebral cortex was most affected, with messenger levels lower than in normal animals at all ages. In more caudal regions differences between control and hypothyroid rats were evident only at the earlier stages of myelination, with spontaneous recovery at later ages. By run on analysis, we found no differences in transcriptional activities of the MAG gene in normal, hypothyroid, or T4-treated rats. Therefore, the effects of hypothyroidism on MAG mRNA and protein levels were most likely caused by decreased mRNA stability. We propose that thyroid hormone contributes to enhanced myelin gene expression by affecting the stability of newly transcribed mRNA in the early phases of myelination. (J. Clin. Invest. 1993.812-818.)

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Developmentally regulated alternative splicing of brain myelin‐associated glycoprotein mRNA is lacking in the quaking mouse

Cited by 56 publications

References 15 publications

Endocytic depletion of L-MAG from CNS myelin in quaking mice.

Endocytic depletion of L-MAG from CNS myelin in quaking mice.

The KH domain protein encoded by quaking functions as a dimer and is essential for notochord development inXenopus embryos

Neonatal hypothyroidism affects the timely expression of myelin-associated glycoprotein in the rat brain.

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