A postnatal switch of CELF and MBNL proteins reprograms alternative splicing in the developing heart.
From a large-scale screen using splicing microarrays and RT-PCR, we identified 63 alternative splicing (AS) events that are coordinated in 3 distinct temporal patterns during mouse heart development. More than half of these splicing transitions are evolutionarily conserved between mouse and chicken. Computational analysis of the introns flanking these splicing events identified enriched and conserved motifs including binding sites for CUGBP and ETR-3-like factors (CELF), muscleblind-like (MBNL) and Fox proteins. We show that CELF proteins are down-regulated >10-fold during heart development, and MBNL1 protein is concomitantly up-regulated nearly 4-fold. Using transgenic and knockout mice, we show that reproducing the embryonic expression patterns for CUGBP1 and MBNL1 in adult heart induces the embryonic splicing patterns for more than half of the developmentally regulated AS transitions. These findings indicate that CELF and MBNL proteins are determinative for a large subset of splicing transitions that occur during postnatal heart development.
Kalsotra
Auinash
A
Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA.
Xiao
Xinshu
X
Ward
Amanda J
AJ
Castle
John C
JC
Johnson
Jason M
JM
Burge
Christopher B
CB
Cooper
Thomas A
TA
D017398:Alternative Splicing; D000818:Animals; D001665:Binding Sites; D000067878:CELF Proteins; D000067879:CELF1 Protein; D002645:Chickens; D004268:DNA-Binding Proteins / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000254:growth & development*; D051379:Mice; D016601:RNA-Binding Proteins / Q000502:physiology*
D000067878:CELF Proteins; D000067879:CELF1 Protein; C502743:CELF1 protein, mouse; C470022:Celf4 protein, mouse; D004268:DNA-Binding Proteins; C479922:Mbnl1 protein, mouse; D016601:RNA-Binding Proteins