Abstract |
We report that mice lacking the heterogeneous nuclear ribonucleoprotein U ( hnRNP U) in the heart develop lethal dilated cardiomyopathy and display numerous defects in cardiac pre-mRNA splicing. Mutant hearts have disorganized cardiomyocytes, impaired contractility, and abnormal excitation-contraction coupling activities. RNA-seq analyses of Hnrnpu mutant hearts revealed extensive defects in alternative splicing of pre-mRNAs encoding proteins known to be critical for normal heart development and function, including Titin and calcium/calmodulin-dependent protein kinase II delta (Camk2d). Loss of hnRNP U expression in cardiomyocytes also leads to aberrant splicing of the pre-mRNA encoding the excitation-contraction coupling component Junctin. We found that the protein product of an alternatively spliced Junctin isoform is N-glycosylated at a specific asparagine site that is required for interactions with specific protein partners. Our findings provide conclusive evidence for the essential role of hnRNP U in heart development and function and in the regulation of alternative splicing.
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Authors | Junqiang Ye, Nadine Beetz, Sean O'Keeffe, Juan Carlos Tapia, Lindsey Macpherson, Weisheng V Chen, Rhonda Bassel-Duby, Eric N Olson, Tom Maniatis |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 112
Issue 23
Pg. E3020-9
(Jun 09 2015)
ISSN: 1091-6490 [Electronic] United States |
PMID | 26039991
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Calcium-Binding Proteins
- Heterogeneous-Nuclear Ribonucleoprotein U
- Membrane Proteins
- Muscle Proteins
- RNA Precursors
- RNA, Messenger
- Asph protein, mouse
- Mixed Function Oxygenases
- Calcium
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Topics |
- Alternative Splicing
(physiology)
- Animals
- Calcium
(metabolism)
- Calcium-Binding Proteins
(metabolism)
- Glycosylation
- Heart
(growth & development, physiology)
- Heterogeneous-Nuclear Ribonucleoprotein U
(genetics, physiology)
- Membrane Proteins
(metabolism)
- Mice
- Mice, Knockout
- Mixed Function Oxygenases
(metabolism)
- Muscle Proteins
(metabolism)
- Mutation
- RNA Precursors
(metabolism)
- RNA, Messenger
(metabolism)
- Sarcomeres
(metabolism)
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