Expression of myelin protein genes in quaking mouse brain

Konat, G.; Trojanowska, Maria; Gantt, G.; Hogan, Edward L.

doi:10.1002/jnr.490200104

Cited by 20 publications

(11 citation statements)

References 22 publications

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“…We surmise that the Northern blot analyses of Fujita et al [21] were insufficiently sensitive to detect both isoforms since they even failed to detect L-MAG in normal adult mice. It is also worth noting that Konat et al [2] have, by Northern blot analysis of mRNA for qk MAG, concluded that the processing of MAG transcripts, at least at day 18 and be yond, appeared to be normal.…”

Section: Discussionmentioning

confidence: 99%

“…Considerable investigation has led to the characterization of many biochem ical, morphological and physiological fea tures of this mutant (studies prior to 1984 have been reviewed [1]. More recent investi gations of gene expression for specific myelin-related proteins have called attention to several aspects of anomalous neural devel opment and dysregulation in myelinogenesis [2][3][4], but the specific genetic target, known to be on chromosome 17, remains elusive.…”

Section: Introductionmentioning

confidence: 99%

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Two Isoforms of Myelin-Associated Glycoprotein Accumulate in <i>Quaking </i>Mice: Only the Large Polypeptide Is Phosphorylated

Braun

Horvath²,

Edwards³

1990

Dev Neurosci

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We have shown that the developmental regulated appearance of the two myelin-associated glycoprotein (MAG) polypeptides in normal mouse brain myelin does not reflect the developmental pattern of differential splicing of primary gene transcripts as determined earlier by RNase protection assays. Contrary to expectation, the large (L-MAG) and small (S-MAG) polypeptides are present in about equal amounts at a relatively early stage of myelination, day 24 or earlier. In quaking (qk) mutant mouse brain myelin, both MAG polypeptides are evident at all ages examined; the relatively greater abundance of S-MAG compared to L-MAG at early ages (days 18 and 22) confirms our earlier observation on in vitro translations of mRNA. At later ages (day 27 and beyond) both isoforms are present in approximately equal amounts. The L-MAG but not the S-MAG polypeptide can be phosphorylated by kinases that are endogenous to isolated qk myelin, analogous to the phosphorylation we have observed in vivo in normal mice and in their isolated myelin.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Two Isoforms of Myelin-Associated Glycoprotein Accumulate in <i>Quaking </i>Mice: Only the Large Polypeptide Is Phosphorylated

Braun

Horvath²,

Edwards³

1990

Dev Neurosci

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“…The nuclear pellet was subsequently homogenized in 5% citric acid and purified as described by Konat et al (1990).…”

Section: Isolation Of Nucleimentioning

confidence: 99%

Cyclic AMP‐induced upregulation of proteolipid protein and myelin associated glycoprotein gene expression in C6 cells

Ye¹,

Kanoh²,

Zhu³

et al. 1992

J of Neuroscience Research

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A model culture system of C6 rat glioma cells was used to test the involvement of cAMP in the regulation of the myelin PLP and MAG genes. The treatment of cells with isoproterenol (10(-5) to 10(-8) M) upregulated the expression of the PLP and MAG genes in a concentration-dependent manner. The mRNA for PLP reached a maximum (sevenfold higher than in control cells) after about 12-24 hr, then declined to approximately fourfold over the control level. The response of MAG gene was delayed by at least 36 hr, and the level of MAG mRNA reached a maximum of approximately 48-fold over the control level on the fourth day in culture. The co-administration of propranolol blocked the effect of isoproterenol, whereas 10(-5) M forskolin simulated the effect of isoproterenol, indicating a role of cAMP in the signal transduction cascades leading to upregulation of the myelin genes. However, the dissimilarity in the timing and the extent of upregulation of the PLP and MAG genes by cAMP-stimulating agents indicate the existence of different intracellular mechanisms for the activation of these two genes. Cycloheximide blocked the stimulatory effect of isoproterenol on both the PLP and MAG genes, indicating that the effect of cAMP on the myelin genes is mediated by protein product(s) of other cAMP-response gene(s).

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“…In the plp gene, two splicing products named PLP and DM20 are produced by choosing different 5Ј splice sites of exon 3 (12). Although several studies of MBP and PLP expression in qk v mice have been reported, these experiments characterized the total gene expression, but not that of individual isoforms (19,20). Thus, it is still not clear whether their alternative splicing is disturbed in the mutant.…”

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confidence: 99%

Function of quaking in myelination: Regulation of alternative splicing

Reed

Grabowski

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

182

214

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Proteomic diversity is frequently achieved by alternative RNAsplicing events that can be fine-tuned in tissue-specific and developmentally regulated ways. Understanding this type of genetic regulation is compelling because of the extensive complexity of alternative splicing found in the nervous system. quaking (qk), one of the classical mouse dysmyelination mutants, is defective for the expression of myelin-associated glycoprotein (MAG), and the misregulation of MAG pre-mRNA alternative splicing is implicated as a causal factor. The qk locus encodes several RNA-binding proteins with heterogeneous nuclear ribonucleoprotein K-type homology, a characteristic of several known alternative splicing regulators. Here we test the nuclear-localized qk isoform (QKI-5) for its ability to regulate alternative splicing of MAG pre-mRNA in transient coexpression assays. QKI-5 exhibits properties of a negative regulator of MAG exon 12 alternative splicing. An intronic sequence element required for the repressive function and binding of QKI-5 is also identified. Direct evidence for irregularities in alternative splicing of MAG and other myelin protein transcripts in the qk mouse is demonstrated.A lternative splicing is a powerful way to regulate gene expression at the posttranscriptional level and to generate protein diversity (1, 2). Understanding the molecular basis of such mechanisms is an urgent challenge, because the number of protein-coding genes in humans has been estimated at barely double the number in Drosophila and Caenorhabditis elegans. Between 35% and 59% of human genes are predicted to generate alternatively spliced mRNA isoforms (3).Mouse quaking (qk), also known as quaking viable (qk v ), is a classical recessive dysmyelination mutation (4). The qk locus produces a diverse set of proteins by alternative splicing (5, 6). They all contain a single heterogeneous nuclear ribonucleoprotein K homology (KH) RNA-binding domain and belong to the evolutionarily conserved signal transduction and activator of RNA (STAR) family (7,8). The first three studied in detail are constructed with the same 311-aa body, but have different carboxyl tails. QKI-5 is the only nuclear isoform and shuttles between the nucleus and cytoplasm (9, 10). The expression of QKI isoforms is developmentally regulated, with QKI-5 being highly expressed throughout the embryogenesis and neonatal stages and decreasing gradually thereafter (7, 9). In postnatal day 14 (P14) mutant mice QKI proteins are decreased exclusively in myelin-forming cells. In addition, the QKI-5 expression level in qk v brain correlates with the severity of dysmyelinating phenotype, suggesting a function of QKI-5 in myelination (9).The relationship between the decreased QKI protein in affected mice and their myelination defects is not understood. It has been shown that several myelin-specific genes are alternatively spliced, including myelin basic protein (MBP), proteolipid protein (PLP), and MAG (11-13). Some splicing events seem to be abnormal in qk v mice. The best-documented c...

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Expression of myelin protein genes in quaking mouse brain

Cited by 20 publications

References 22 publications

Two Isoforms of Myelin-Associated Glycoprotein Accumulate in <i>Quaking </i>Mice: Only the Large Polypeptide Is Phosphorylated

Two Isoforms of Myelin-Associated Glycoprotein Accumulate in <i>Quaking </i>Mice: Only the Large Polypeptide Is Phosphorylated

Cyclic AMP‐induced upregulation of proteolipid protein and myelin associated glycoprotein gene expression in C6 cells

Function of quaking in myelination: Regulation of alternative splicing

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