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Dynamic balance between activation and repression regulates pre‐mRNA alternative splicing during heart development
Author(s) -
Ladd Andrea N.,
Stenberg Myrna G.,
Swanson Maurice S.,
Cooper Thomas A.
Publication year - 2005
Publication title -
developmental dynamics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.634
H-Index - 141
eISSN - 1097-0177
pISSN - 1058-8388
DOI - 10.1002/dvdy.20382
Subject(s) - biology , rna splicing , alternative splicing , exon , rna binding protein , sr protein , microbiology and biotechnology , splicing factor , polypyrimidine tract binding protein , messenger rna , genetics , gene , rna
Cardiac troponin T (cTNT) exon 5 splicing is developmentally regulated such that it is included in embryonic but not adult heart. CUG‐BP and ETR‐3‐like factor (CELF) proteins promote exon inclusion, whereas polypyrimidine tract binding protein (PTB) and muscleblind‐like (MBNL) proteins repress inclusion. In this study, we addressed what happens to these regulatory proteins during heart development to shift the regulatory balance of cTNT alternative splicing. Using dominant‐negative proteins, we found that both CELF and PTB activities are required for appropriate splicing in cardiomyocytes. Two CELF proteins, CUG‐BP and ETR‐3, are nuclear and cytoplasmic in embryonic heart but are down‐regulated in adult heart concomitant with loss of exon inclusion. In contrast, PTB and MBNL1 are expressed throughout heart development. The patterns of cTNT splicing and expression of its regulatory factors are conserved between mouse and chicken. Thus, alternative splicing is determined by a balance between positive and negative regulation, and modulation of expression levels of auxiliary splicing regulators may drive developmental splicing changes. ETR‐3 and CUG‐BP proteins are also down‐regulated in other tissues during development, suggesting that CELF proteins play a broad role in developmental splicing regulation. Developmental Dynamics, 2005. © 2005 Wiley‐Liss, Inc.