Dynamic antagonism between ETR-3 and PTB regulates cell type-specific alternative splicing.
Inclusion of cardiac troponin T (cTNT) exon 5 in embryonic muscle requires conserved flanking intronic elements (MSEs). ETR-3, a member of the CELF family, binds U/G motifs in two MSEs and directly activates exon inclusion in vitro. Binding and activation by ETR-3 are directly antagonized by polypyrimidine tract binding protein (PTB). We use dominant-negative mutants to demonstrate that endogenous CELF and PTB activities are required for MSE-dependent activation and repression in muscle and nonmuscle cells, respectively. Combined use of CELF and PTB dominant-negative mutants provides an in vivo demonstration that antagonistic splicing activities exist within the same cells. We conclude that cell-specific regulation results from the dominance of one among actively competing regulatory states rather than modulation of a nonregulated default state.
Charlet-B
Nicolas
N
Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Logan
Penny
P
Singh
Gopal
G
Cooper
Thomas A
TA
D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D000067878:CELF Proteins; D002642:Chick Embryo; D002645:Chickens; D017124:Conserved Sequence / Q000235:genetics; D005091:Exons / Q000235:genetics; D006801:Humans; D018482:Muscle, Skeletal / Q000196:embryology / Q000502:physiology; D009419:Nerve Tissue Proteins; D038941:Polypyrimidine Tract-Binding Protein; D011485:Protein Binding; D016601:RNA-Binding Proteins / Q000378:metabolism*; D012261:Ribonucleoproteins / Q000378:metabolism*; D020107:Troponin T / Q000235:genetics / Q000378:metabolism
D022762:CCAAT-Enhancer-Binding Proteins; D000067878:CELF Proteins; C117363:CELF2 protein, human; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; D020107:Troponin T; D038941:Polypyrimidine Tract-Binding Protein