Disrupted Prenatal RNA Processing and Myogenesis in Congenital Myotonic Dystrophy
Başlık:
Disrupted Prenatal RNA Processing and Myogenesis in Congenital Myotonic Dystrophy
Yazar:
Thomas, James Douglas, author.
ISBN:
9780438122246
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (207 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-11(E), Section: B.
Advisors: Maurice S. Swanson.
Özet:
Myotonic dystrophy type 1 (DM1) is a CTG microsatellite expansion (CTG exp) disorder caused by expression of CUGexp 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 mis-regulated in adult-onset DM1, dysregulation is significantly more severe in CDM. Furthermore, analysis of alternative splicing during human myogenesis reveals CDM-relevant exons undergo prenatal RNA isoform transitions and are predicted to be disrupted by CUGexp-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. These findings are supported by neonatal histopathology in hindlimb and diaphragm musculature as well as dramatic perinatal lethality attributed to respiratory insufficiency. Using RNA-seq and comparative transcriptomics, we identified hundreds of abnormally spliced exons conserved between Mbnl knockout and CDM patient muscle. Furthermore, Mbnl triple knockout mice recapitulate biological pathways disrupted in CDM, including hypoxia induced gene expression. This study demonstrates RNA mis-processing is a major pathogenic factor in CDM and provides novel mouse models to further examine roles for co/post-transcriptional gene regulation during development.
Notlar:
School code: 0070
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(696653.1) | 696653-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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