Splice site selection in the proteolipid protein (PLP) gene transcript and primary structure of the DM-20 protein of central nervous system myelin.

Nave, Klaus‐Armin; Lai, Cary; Bloom, Floyd E.; Milner, Robert J.

doi:10.1073/pnas.84.16.5665

Cited by 292 publications

(222 citation statements)

References 45 publications

(42 reference statements)

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“…Notably, several other myelin genes are also alternatively spliced (12,13). Among them, PLP and MBP represent possible targets of QKI-5.…”

Section: Resultsmentioning

confidence: 99%

“…Point mutations and misregulation of the plp gene cause dysmyelination in both mice and humans (17,18). 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).…”

mentioning

confidence: 99%

“…It has been shown that several myelin-specific genes are alternatively spliced, including myelin basic protein (MBP), proteolipid protein (PLP), and MAG (11)(12)(13). Some splicing events seem to be abnormal in qk v mice.…”

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confidence: 99%

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Function of quaking in myelination: Regulation of alternative splicing

Reed

Grabowski

et al. 2002

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

177

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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“…Notably, several other myelin genes are also alternatively spliced (12,13). Among them, PLP and MBP represent possible targets of QKI-5.…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Function of quaking in myelination: Regulation of alternative splicing

Reed

Grabowski

et al. 2002

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

177

214

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“…Proteolipid protein (PLP) and DM20, which is an alternatively spliced isoform of the PLP gene (Nave et al, 1987), constitute ϳ50% of the protein in myelin (Greenfield et al, 1971). It is generally accepted that one of the biological functions of PLP is to maintain the structural integrity of the myelin membrane (Duncan et al, 1987;Boison and Stoffel, 1994;Nave, 1994;Boison et al, 1995).…”

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confidence: 99%

Proteolipid Protein Regulates the Survival and Differentiation of Oligodendrocytes

Yang

Skoff

1997

J. Neurosci.

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Proteolipid protein (PLP) has been postulated to play a critical role in the early differentiation of oligodendrocytes (OLs) in addition to its known role as a structural component of myelin.To identify this early function, we blocked the synthesis of PLP in glial cultures with antisense oligodeoxynucleotides that targeted the PLP initiation codon. Primary glial cultures were incubated with phosphorothioate-protected oligodeoxynucleotides (S-ODNs) for up to 11 d. PLP in OLs was reduced Ͼ90%. OLs treated with antisense S-ODNs appeared strikingly healthy as judged by (1) immunocytochemical staining for myelin glycolipids and myelin basic protein, (2) their prolonged survival compared with untreated cultures, and (3) their ability to reestablish membrane sheets after removal of the S-ODNs.Our studies show that PLP is required for elaboration and stability of the myelin membrane sheets made by most OLs, but it is not necessary for the network of processes established by OLs. More importantly, the number of OLs in the antisensetreated cultures was nearly sevenfold greater after a 10 -11 d incubation with S-ODNs than in control cultures. The number of proliferating OL progenitors was not increased in the antisensetreated cultures, indicating that the increase in the number of OLs was attributable to prolonged OL survival. The tissue culture studies reveal that the absence of PLP/DM20 has the positive effect of promoting OL survival but the negative effect of preventing their full differentiation. This finding clarifies many of the paradoxical findings seen in the PLP mutants, the PLP overexpressers, and the PLP Ϫ animals.

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“…The PLP gene, which encodes two major components of the CNS myelin, PLP and DM 20 (Nave et al 1987), is located in Xq22.1 (Mattei et al 1986), and is thus within the interval to which the present syndrome has been as signed. M utations in the PLP gene have been found in a number of patients with Pelizaeus-M erzbacher disease (PMD, MIM no.…”

Section: Resultsmentioning

confidence: 99%

Localization of the gene (or genes) for a syndrome with X-linked mental retardation, ataxia, weakness, hearing impairment, loss of vision and a fatal course in early childhood

et al. 1996

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Linkage analysis is described in a family with X-linked m ental retardation, ataxia, weakness, floppiness, delayed m otor developm ent, absence of deep tendon re flexes, hearing im pairm ent and loss of vision (M IM no. 301835). The disease has a fatal course due to the suscep tibility of the patients to infections, especially of the res piratory tract. Clinical signs indicate impairment of the posterior columns, peripheral m otor and sensory neurons and the second and eighth cranial nerves and/or their nu clei. The involvem ent of the posterior columns of the spinal cord is further suggested by the almost complete absence of myelinated fibers therein. We localized the re sponsible gene(s) to X q21.33-q24 betw een D X S 1231 and DXS 1001 with a m axim um lod score o f 6.97. The proteolipid protein gene, which codes for two myelin proteins of the central nervous system and is located in this region, was considered as a candidate gene for this disorder. However, no m utations were found in the protein-coding part of this gene.

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Splice site selection in the proteolipid protein (PLP) gene transcript and primary structure of the DM-20 protein of central nervous system myelin.

Cited by 292 publications

References 45 publications

Function of quaking in myelination: Regulation of alternative splicing

Function of quaking in myelination: Regulation of alternative splicing

Proteolipid Protein Regulates the Survival and Differentiation of Oligodendrocytes

Localization of the gene (or genes) for a syndrome with X-linked mental retardation, ataxia, weakness, hearing impairment, loss of vision and a fatal course in early childhood

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