SRp38 regulates alternative splicing and is required for Ca(2+) handling in the embryonic heart.
SRp38 is an atypical SR protein splicing regulator. To define the functions of SRp38 in vivo, we generated SRp38 null mice. The majority of homozygous mutants survived only until E15.5 and displayed multiple cardiac defects. Evaluation of gene expression profiles in the SRp38(-/-) embryonic heart revealed a defect in processing of the pre-mRNA encoding cardiac triadin, a protein that functions in regulation of Ca(2+) release from the sarcoplasmic reticulum during excitation-contraction coupling. This defect resulted in significantly reduced levels of triadin, as well as those of the interacting protein calsequestrin 2. Purified SRp38 was shown to bind specifically to the regulated exon and to modulate triadin splicing in vitro. Extending these results, isolated SRp38(-/-) embryonic cardiomyocytes displayed defects in Ca(2+) handling compared with wild-type controls. Taken together, our results demonstrate that SRp38 regulates cardiac-specific alternative splicing of triadin pre-mRNA and, reflecting this, is essential for proper Ca(2+) handling during embryonic heart development.
Feng
Ying
Y
Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
Valley
Matthew T
MT
Lazar
Josef
J
Yang
Allison L
AL
Bronson
Roderick T
RT
Firestein
Stuart
S
Coetzee
William A
WA
Manley
James L
JL
D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002469:Cell Separation; D002645:Chickens; D004487:Edema / Q000196:embryology; D020964:Embryo Loss / Q000378:metabolism; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000378:metabolism; D005091:Exons / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000196:embryology* / Q000235:genetics*; D008099:Liver / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D009363:Neoplasm Proteins / Q000172:deficiency / Q000378:metabolism*; D011485:Protein Binding; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D014162:Transfection
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C485446:Fusip1 protein, mouse; D009124:Muscle Proteins; D009363:Neoplasm Proteins; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; C070048:triadin; D002118:Calcium