hnRNP U protein is required for normal pre-mRNA splicing and postnatal heart development and function.

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.

• 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)

Chemical References

• Calcium-Binding Proteins
• Heterogeneous-Nuclear Ribonucleoprotein U
• Membrane Proteins
• Muscle Proteins
• RNA Precursors
• RNA, Messenger
• Asph protein, mouse
• Mixed Function Oxygenases
• Calcium

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)