Roles for RNA-binding proteins in development and disease

Brinegar, Amy E.; Cooper, Thomas A.

doi:10.1016/j.brainres.2016.02.050

Cited by 135 publications

(114 citation statements)

References 80 publications

(97 reference statements)

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“…This delicate system is often disrupted in human disease (Brinegar and Cooper, 2016; Scotti and Swanson, 2015) and has been a major focal point for interpreting mutations that are identified through whole-genome medicine (Xiong et al, 2015). Currently, our ability to predict exon-intron junctions from the primary genomic sequence is limited, in part due to the loose consensus sequence of most splicing proteins.…”

Section: Introductionmentioning

confidence: 99%

PTBP1 and PTBP2 Repress Nonconserved Cryptic Exons

et al. 2016

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The fidelity of RNA splicing is maintained by a network of factors, but the molecular mechanisms that govern this process have yet to be fully elucidated. We previously found that TDP-43, an RNA-binding protein implicated in neurodegenerative disease, utilizes UG microsatellites to repress nonconserved cryptic exons and prevent their incorporation into mRNA. Here, we report that two well characterized splicing factors, polypyrimidine tract-binding protein 1 (PTBP1) and polypyrimidine tract-binding protein 2 (PTBP2), are also nonconserved cryptic exon repressors. In contrast to TDP-43, PTBP1 and PTBP2 utilize CU microsatellites to repress both conserved tissue-specific exons as well as nonconserved cryptic exons. Analysis of these conserved splicing events suggests that PTBP1 and PTBP2 repression is titrated to generate the transcriptome diversity required for neuronal differentiation. Together, we establish that PTBP1 and PTBP2 are members of a family of cryptic exon repressors.

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Section: Introductionmentioning

confidence: 99%

PTBP1 and PTBP2 Repress Nonconserved Cryptic Exons

et al. 2016

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“…Translational control is essential for numerous processes in development and learning, and it also impacts disease progression (Brinegar and Cooper, 2016). The PUF family of proteins is an important class of RNA-binding regulatory proteins that are conserved in most eukaryotes (Quenault et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Dynein light chain DLC-1 promotes localization and function of the PUF protein FBF-2 in germline progenitor cells

et al. 2016

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PUF family translational repressors are conserved developmental regulators, but the molecular function provided by the regions flanking the PUF RNA-binding domain is unknown. In C. elegans, the PUF proteins FBF-1 and FBF-2 support germline progenitor maintenance by repressing production of meiotic proteins and use distinct mechanisms to repress their target mRNAs. We identify dynein light chain DLC-1 as an important regulator of FBF-2 function. DLC-1 directly binds to FBF-2 outside of the RNA-binding domain and promotes FBF-2 localization and function. By contrast, DLC-1 does not interact with FBF-1 and does not contribute to FBF-1 activity. Surprisingly, we find that the contribution of DLC-1 to FBF-2 activity is independent of the dynein motor. Our findings suggest that PUF protein localization and activity are mediated by sequences flanking the RNA-binding domain that bind specific molecular partners. Furthermore, these results identify a new role for DLC-1 in posttranscriptional regulation of gene expression.

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“…For example, aberrant expression of RBFOX2 inhibits myoblast fusion, while loss of RBFOX1 is implicated in later stages of muscle development, including sarcomerogenesis and functional muscle maintenance (Singh et al 2014;Pedrotti et al 2015). In fact, RBPs often coordinate their activities to control alternative splicing (AS) patterns in health and disease (Brinegar and Cooper 2016). To date, very little is known about the roles of RBP interactions and alternative RNA processing in neonatal myopathies such as congenital myotonic dystrophy (CDM), where failure of normal muscle development is a characteristic feature.…”

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confidence: 99%

Disrupted prenatal RNA processing and myogenesis in congenital myotonic dystrophy

et al. 2017

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Myotonic dystrophy type 1 (DM1) is a CTG microsatellite expansion (CTG exp ) disorder caused by expression of CUG exp RNAs. These mutant RNAs alter the activities of RNA processing factors, including MBNL proteins, leading to re-expression of fetal isoforms in adult tissues and DM1 pathology. While this pathogenesis model accounts for adult-onset disease, the molecular basis of congenital DM (CDM) is unknown. Here, we test the hypothesis that disruption of developmentally regulated RNA alternative processing pathways contributes to CDM disease. We identify prominent alternative splicing and polyadenylation abnormalities in infant CDM muscle, and, although most are also misregulated in adult-onset DM1, dysregulation is significantly more severe in CDM. Furthermore, analysis of alternative splicing during human myogenesis reveals that CDM-relevant exons undergo prenatal RNA isoform transitions and are predicted to be disrupted by CUG exp -associated mechanisms in utero. To test this possibility and the contribution of MBNLs to CDM pathogenesis, we generated mouse Mbnl double (Mbnl1; Mbnl2) and triple (Mbnl1; Mbnl2; Mbnl3) muscle-specific knockout models that recapitulate the congenital myopathy, gene expression, and spliceopathy defects characteristic of CDM. This study demonstrates that RNA misprocessing is a major pathogenic factor in CDM and provides novel mouse models to further examine roles for cotranscriptional/post-transcriptional gene regulation during development.

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Roles for RNA-binding proteins in development and disease

Cited by 135 publications

References 80 publications

PTBP1 and PTBP2 Repress Nonconserved Cryptic Exons

PTBP1 and PTBP2 Repress Nonconserved Cryptic Exons

Dynein light chain DLC-1 promotes localization and function of the PUF protein FBF-2 in germline progenitor cells

Disrupted prenatal RNA processing and myogenesis in congenital myotonic dystrophy

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