STAR proteins quaking-6 and GLD-1 regulate translation of the homologues GLI1 and tra-1 through a conserved RNA 3′UTR-based mechanism

Lakiza, Olga; Frater, Leah; Yoo, Youngdong; Villavicencio, Elisabeth H.; Walterhouse, David; Goodwin, Elizabeth B.; Iannaccone, Philip M.

doi:10.1016/j.ydbio.2005.08.038

Cited by 23 publications

(9 citation statements)

References 55 publications

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“…Furthermore, we show that the gli2a 3ЈUTR confers sensitivity to QkA in vivo (sensor assay) and provide evidence for in vivo functional interaction between QkA and gli2a (the analysis of the yot mutant). Interestingly, the capacity of mouse Qk and the related C. elegans GLD-1 to regulate Gli1 (or C. elegans tra-1) by binding to their QREs and repressing translation has been described (Lakiza et al, 2005). Our data are consistent with an action at the translational level, although they support an activation rather than a repression, potentially stemming from a difference in the QRE-encompassing region or structural differences between zebrafish QkA and GLD-1.…”

Section: Fine-tuning Of Thesupporting

confidence: 74%

Fine-tuning of Hh signaling by the RNA-binding protein Quaking to control muscle development

et al. 2011

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SUMMARYThe development of the different muscles within the somite is a complex process that involves the Hedgehog (Hh) signaling pathway. To specify the proper number of muscle cells and organize them spatially and temporally, the Hh signaling pathway needs to be precisely regulated at different levels, but only a few factors external to the pathway have been described. Here, we report for the first time the role of the STAR family RNA-binding protein Quaking A (QkA) in somite muscle development. We show in zebrafish that the loss of QkA function affects fast muscle fiber maturation as well as Hh-induced muscle derivative specification and/or morphogenesis. Mosaic analysis reveals that fast fiber maturation depends on the activity of QkA in the environment of fast fiber progenitors. We further show that Hh signaling requires QkA activity for muscle development. By an in silico approach, we screened the 3ЈUTRs of known Hh signaling component mRNAs for the Quaking response element and found the transcription factor Gli2a, a known regulator of muscle fate development. Using destabilized GFP as a reporter, we show that the gli2a mRNA 3ЈUTR is a functional QkA target. Consistent with this notion, the loss of QkA function rescued slow muscle fibers in yot mutant embryos, which express a dominant-negative Gli2a isoform. Thus, our results reveal a new mechanism to ensure muscle cell fate diversity by fine-tuning of the Hh signaling pathway via RNA-binding proteins.

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Section: Fine-tuning Of Thesupporting

confidence: 74%

Fine-tuning of Hh signaling by the RNA-binding protein Quaking to control muscle development

et al. 2011

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“…For example, the branchpoint sequence URAY (in yeast, UACUAAC), found near exons and utilized in constitutive splicing during the first catalytic step, is bound by SF1 (in yeast, BBP1) to recruit the splicing machinery to the intron (Kramer 1992;Liu et al 2001). The response element for QK and its C. elegans homolog GLD-1 ) has been found in 3 ′ UTRs, where it regulates mRNA stability, localization, and translation (Saccomanno et al 1999;Li et al 2000;Lakiza et al 2005;Zhao et al 2010;Zearfoss et al 2011). We found that both QK and SF1 bound the ACUAAlike sequences downstream from Capzb exon 9 by RNA affinity chromatography (Fig.…”

Section: Qk Rna-binding Proteins Are Ancient Regulators Of Fundamentamentioning

confidence: 70%

Quaking and PTB control overlapping splicing regulatory networks during muscle cell differentiation

Hall

Nagel

Fagg

et al. 2013

RNA

140

164

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Alternative splicing contributes to muscle development, but a complete set of muscle-splicing factors and their combinatorial interactions are unknown. Previous work identified ACUAA ("STAR" motif) as an enriched intron sequence near musclespecific alternative exons such as Capzb exon 9. Mass spectrometry of myoblast proteins selected by the Capzb exon 9 intron via RNA affinity chromatography identifies Quaking (QK), a protein known to regulate mRNA function through ACUAA motifs in 3 ′ UTRs. We find that QK promotes inclusion of Capzb exon 9 in opposition to repression by polypyrimidine tract-binding protein (PTB). QK depletion alters inclusion of 406 cassette exons whose adjacent intron sequences are also enriched in ACUAA motifs. During differentiation of myoblasts to myotubes, QK levels increase two-to threefold, suggesting a mechanism for QK-responsive exon regulation. Combined analysis of the PTB-and QK-splicing regulatory networks during myogenesis suggests that 39% of regulated exons are under the control of one or both of these splicing factors. This work provides the first evidence that QK is a global regulator of splicing during muscle development in vertebrates and shows how overlapping splicing regulatory networks contribute to gene expression programs during differentiation.

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“…In addition to the well-characterized function of QKI in controlling mRNA stability in OLs and CNS myelin development (21,22,26), QKI-6 was reported to suppress translation of reporter in vitro and in transfected cells (38,39), although no direct evidence has demonstrated the role of QKI as a translation suppressor in vivo in mammals. In the qk v /qk v mutant, deficiency of QKI leads to increased expression of hnRNPA1 protein without affecting the level of hnRNPA1 mRNA (Fig.…”

Section: Discussionmentioning

confidence: 99%

Quaking I controls a unique cytoplasmic pathway that regulates alternative splicing of myelin-associated glycoprotein

Zhao¹,

Mandler²,

Yun

et al. 2010

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

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Precise control of alternative splicing governs oligodendrocyte (OL) differentiation and myelination in the central nervous system (CNS). A well-known example is the developmentally regulated expression of splice variants encoding myelin-associated glycoprotein (MAG), which generates two protein isoforms that associate with distinct cellular components crucial for axon-glial recognition during myelinogenesis and axon-myelin stability. In the quakingviable (qk v ) hypomyelination mutant mouse, diminished expression of isoforms of the selective RNA-binding protein quaking I (QKI) leads to severe dysregulation of MAG splicing. The nuclear isoform QKI-5 was previously shown to bind an intronic element of MAG and modulate alternative exon inclusion from a MAG minigene reporter. Thus, QKI-5 deficiency was thought to underlie the defects of MAG splicing in the qk v mutant. Surprisingly, we found that transgenic expression of the cytoplasmic isoform QKI-6 in the qk v OLs completely rescues the dysregulation of MAG splicing without increasing expression or nuclear abundance of QKI-5. In addition, cytoplasmic QKI-6 selectively associates with the mRNA that encodes heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), a well-characterized splicing factor. Furthermore, QKI deficiency in the qk v mutant results in abnormally enhanced hnRNPA1 translation and overproduction of the hnRNPA1 protein but not hnRNPA1 mRNA, which can be successfully rescued by the QKI-6 transgene. Finally, we show that hnRNPA1 binds MAG pre-mRNA and modulates alternative inclusion of MAG exons. Together, these results reveal a unique cytoplasmic pathway in which QKI-6 controls translation of the splicing factor hnRNPA1 to govern alternative splicing in CNS myelination.selective RNA-binding protein QKI | heterogeneous nuclear ribonucleoprotein A1 | myelin development | 3′-UTR | translation regulation M yelination enables rapid conduction of nerve impulses and protects neuronal axons from extracellular insults, which is essential for the development and function of the central nervous system (CNS) (1). Oligodendrocytes (OLs) are responsible for CNS myelination, in which precise expression of OL-specific genes governs the formation and maintenance of CNS myelin (2, 3). Nearly all transcripts encoding myelin-specific structural proteins undergo extensive alternative splicing that is vigorously regulated during myelin development (4). As a result, the abundance of functionally distinct splice variants is markedly altered. A well-known example is the developmentally regulated alternative splicing of the pre-mRNA encoding myelin-associated glycoprotein (MAG), which generates two isoforms that are localized at the periaxonal membrane and mediate reciprocal signals toward axons and OLs (5). In rodents, exclusion of exon 12 generates the large MAG protein (L-MAG) predominantly expressed in the juvenile CNS, whereas inclusion of exon 12 introduces an in-frame stop codon, giving rise to the small MAG protein (S-MAG) mainly in the peripheral nervous system (PNS)...

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STAR proteins quaking-6 and GLD-1 regulate translation of the homologues GLI1 and tra-1 through a conserved RNA 3′UTR-based mechanism

Cited by 23 publications

References 55 publications

Fine-tuning of Hh signaling by the RNA-binding protein Quaking to control muscle development

Fine-tuning of Hh signaling by the RNA-binding protein Quaking to control muscle development

Quaking and PTB control overlapping splicing regulatory networks during muscle cell differentiation

Quaking I controls a unique cytoplasmic pathway that regulates alternative splicing of myelin-associated glycoprotein

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