Deletion of a splicing enhancer disrupts PLP1/DM20 ratio and myelin stability

Wang, Erming; Dimova, Neviana; Sperle, Karen; Huang, Zhong; Lock, Leslie F.; McCulloch, M. C.; Edgar, Julia M.; Hobson, Grace M.; Cambi, Franca

doi:10.1016/j.expneurol.2008.09.001

Cited by 25 publications

(48 citation statements)

References 35 publications

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“…The G-rich enhancers, G1M2 and ISE, play a critical role in the selection of the DM20 and PLP 5Ј splice sites, respectively, and regulate the developmental increase in the PLP/DM20 ratio and the abundance of these major central nervous system myelin proteins (25,27,30). Tight regulation of the PLP/ DM20 ratio is critical for brain development and function (26,28,29).…”

Section: Discussionmentioning

confidence: 99%

“…The ISE is a critical enhancer of PLP splicing and spans G runs that are essential for its enhancer function and are similar in configuration to M2 (26,27,30). Deletion of the ISE causes a neurological disorder in humans and in a knockin mouse (26,30).…”

Section: Recruitment Of U1snrna To Plp 5јss Does Not Depend On Its Asmentioning

confidence: 99%

“…Deletion of the ISE causes a neurological disorder in humans and in a knockin mouse (26,30). To elucidate the ISE-mediated regulation of PLP and gain insight into disease mechanisms, we tested the role of the ISE in the recruitment of U1snRNA to the PLP 5Јss.…”

Section: Recruitment Of U1snrna To Plp 5јss Does Not Depend On Its Asmentioning

confidence: 99%

“…Tight regulation of the PLP/DM20 ratio is critical for brain development and function (26,28,29). Deletion of the ISE and mutations that strengthen the DM20 5Ј splice site impair the developmental increase in the PLP/DM20 ratio in vivo, resulting in the reduction of the PLP product, which ultimately manifests itself as a neurological disorder in humans and mice (26,30). We have previously shown that hnRNPH and hnRNPF regulate the PLP/DM20 ratio mostly by recruitment of U1snRNP through G1 and M2 located downstream of the DM20 5Ј splice site.…”

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confidence: 99%

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G Run-mediated Recognition of Proteolipid Protein and DM20 5′ Splice Sites by U1 Small Nuclear RNA Is Regulated by Context and Proximity to the Splice Site

Wang

Mueller

Hertel

et al. 2011

Journal of Biological Chemistry

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Highly conserved G runs, G1M2 and ISE, regulate the proteolipid protein (PLP)/DM20 ratio. We have investigated recruitment of U1 small nuclear ribonuclear protein (snRNP) by G1M2 and ISE and examined the effect of splice site strength, distance, and context on G run function. G1M2 is necessary for initial recruitment of U1snRNP to the DM20 5 splice site independent of the strength of the splice site. G1M2 regulates E complex formation and supports DM20 splicing when functional U1snRNP is reduced. By contrast, the ISE is not required for the initial recruitment of U1snRNP to the PLP 5 splice site. However, in close proximity to either the DM20 or the PLP 5 splice site, the ISE recruits U1snRNP to both splice sites. The ISE enhances DM20 splicing, whereas close to the PLP 5 splice site, it inhibits PLP splicing. Splicing enhancement and inhibition are mediated by heterogeneous nuclear ribonuclear protein (hnRNP)H/F. The data show that recognition of the DM20 5 splice site depends on G run-mediated recruitment of U1snRNA, whereas a complex interaction between the ISE G runs, context and position determines the functional outcome on splicing. The data suggest that different mechanisms underlie G run-mediated recognition of 5 splice sites and that context and position play a critical role.Alternative splicing is broadly utilized to generate multiple protein isoforms from a single transcript in a cell-and development-dependent fashion. Genome-wide analyses have shown that alternatively spliced sites are generally weak and that flanking regulatory sequences orchestrate their selection through the interaction with auxiliary splicing factors (for review, see Refs. 1 and 2).Removal of introns from pre-mRNAs takes place within the spliceosome, a ribonuclear complex of RNA, and proteins whose assembly occurs in a stepwise fashion (reviewed in Refs. 3-5). The first step is the formation of the commitment complex, or E complex, that contains the U1snRNP bound to the 5Ј splice site, U2AF bound to the 3Ј acceptor site and at least one member of the SR (serine arginine) proteins. The second step is the formation of the prespliceosome, termed complex A, characterized by the ATP-dependent addition of U2 snRNP. Next, U1 snRNP is replaced by U5 and U6 snRNPs, which base pair with the 5Ј splice site, and the splicing reaction is completed (6, 7).U1snRNP is composed of the U1snRNA, U1-specific proteins (U1 70K, U1A, and U1C), and general Sm spliceosomal proteins that are also present in the U2, U5, and U6 snRNP complexes (8). The recognition of the 5Ј splice site by the RNA moiety of the U1snRNP, through direct base pairing between the 5Ј end of the U1snRNA and the 5Ј splice site of the pre-RNA, commits the pre-RNA to splicing. However, in some genes, interactions other than direct base pairing of the U1snRNA with the 5Ј splice site contribute significantly to the first step of splicing, and removal of the first 7 nucleotides of the U1snRNA does not prevent formation of the E complex (9 -11). G runs, of which the G triplet is the basi...

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Section: Discussionmentioning

confidence: 99%

Section: Recruitment Of U1snrna To Plp 5јss Does Not Depend On Its Asmentioning

confidence: 99%

Section: Recruitment Of U1snrna To Plp 5јss Does Not Depend On Its Asmentioning

confidence: 99%

mentioning

confidence: 99%

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G Run-mediated Recognition of Proteolipid Protein and DM20 5′ Splice Sites by U1 Small Nuclear RNA Is Regulated by Context and Proximity to the Splice Site

Wang

Mueller

Hertel

et al. 2011

Journal of Biological Chemistry

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“…Once damage to myelin by as-yet-undefined triggers has occurred, and full-length PLP has been presented, these specific autoreactive T cells may be activated and gain access to the CNS, where they can initiate an inflammatory response and thus contribute to MS. 90 PLP/DM20 alternative splicing has been characterized in detail. [86][87][88][89] Several cis-acting regulatory elements, including G-rich sequences, have been found in exon 3B. Two of these G-rich elements, named G 1 and M2, bind hnRNPs H and F, which recruit U1 snRNP to the DM20 5' splice site and regulate the PLP/DM20 ratio.…”

Section: Other Autoimmune Diseasesmentioning

confidence: 99%

Alternative splicing in multiple sclerosis and other autoimmune diseases

et al. 2010

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The QKI‐PLP pathway controls SIRT2 abundance in CNS myelin

Zhu

Zhao

Wang

et al. 2011

Glia

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Sirtuin 2 (SIRT2), a NAD-dependent deacetylase expressed by oligodendrocytes (OLs), the myelin-producing cells of the central nervous system (CNS), is markedly up-regulated during active myelination (Li et al. 2007; Southwood et al. 2007; Werner et al. 2007). SIRT2 is a component of the myelin proteome and is severely reduced in the Plp1 knockout mouse brain, in which both PLP and DM20 are absent (Werner et al. 2007). The mechanisms that regulate SIRT2 expression in OLs and myelin remain to be investigated. We report for the first time that the expression of SIRT2 is regulated by the QKI-dependent pathway and this effect is mediated through selective regulation of PLP. In the homozygous quakingviable (qkv/qkv) mutant mouse that harbors QKI deficiency in OLs (Bockbrader and Feng 2008; Ebersole et al. 1996; Hardy et al. 1996), PLP, but not DM20 mRNA, was selectively down-regulated and SIRT2 protein was severely reduced while SIRT2 mRNA expression was unaffected. Expression of the cytoplasmic isoform QKI6 in OLs (Zhao et al. 2006) rescued SIRT2 expression in the qkv/qkv mutant concomitantly with restoration of PLP expression. Moreover, SIRT2 protein is diminished in myelin tracts and compact myelin of the PLP-ISEdel mutant brain, in which PLP protein but not DM20 is selectively reduced (Wang et al. 2008). In contrast, SIRT2 expression and its cellular function in regulating process complexity are not affected by the absence of PLP in PLP-ISEdel non-myelinating oligodendrocytes. Collectively, our results indicate that the abundance of SIRT2 in myelin is dependent on PLP, but not DM20.

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Deletion of a splicing enhancer disrupts PLP1/DM20 ratio and myelin stability

Cited by 25 publications

References 35 publications

G Run-mediated Recognition of Proteolipid Protein and DM20 5′ Splice Sites by U1 Small Nuclear RNA Is Regulated by Context and Proximity to the Splice Site

G Run-mediated Recognition of Proteolipid Protein and DM20 5′ Splice Sites by U1 Small Nuclear RNA Is Regulated by Context and Proximity to the Splice Site

Alternative splicing in multiple sclerosis and other autoimmune diseases

The QKI‐PLP pathway controls SIRT2 abundance in CNS myelin

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