The CELF Family of RNA Binding Proteins Is Implicated in Cell-Specific and Developmentally Regulated Alternative Splicing

doi:10.1128/MCB.21.4.1285-1296.2001

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Molecular and Cellular Biology, February 2001, p. 1285-1296, Vol. 21, No. 4
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.4.1285-1296.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

The CELF Family of RNA Binding Proteins Is Implicated in Cell-Specific and Developmentally Regulated Alternative Splicing

Andrea N. Ladd, Nicolas Charlet-B., and Thomas A. Cooper^*

Department of Pathology, Baylor College of Medicine, Houston, Texas 77030

Received 13 September 2000/Returned for modification 20 October 2000/Accepted 9 November 2000

Alternative splicing of cardiac troponin T (cTNT) exon 5 undergoes a developmentally regulated switch such that exon inclusionpredominates in embryonic, but not adult, striated muscle. Wepreviously described four muscle-specific splicing enhancers (MSEs)within introns flanking exon 5 in chicken cTNT that are both necessaryand sufficient for exon inclusion in embryonic muscle. We alsodemonstrated that CUG-binding protein (CUG-BP) binds a conservedCUG motif within a human cTNT MSE and positively regulates MSE-dependentexon inclusion. Here we report that CUG-BP is one of a novel familyof developmentally regulated RNA binding proteins that includesembryonically lethal abnormal vision-type RNA binding protein3 (ETR-3). This family, which we call CELF proteins for CUG-BP-and ETR-3-like factors, specifically bound MSE-containing RNAsin vitro and activated MSE-dependent exon inclusion of cTNT minigenesin vivo. The expression of two CELF proteins is highly restrictedto brain. CUG-BP, ETR-3, and CELF4 are more broadly expressed,and expression is developmentally regulated in striated muscleand brain. Changes in the level of expression and isoforms ofETR-3 in two different developmental systems correlated with regulatedchanges in cTNT splicing. A switch from cTNT exon skipping toinclusion tightly correlated with induction of ETR-3 protein expressionduring differentiation of C2C12 myoblasts. During heart development,the switch in cTNT splicing correlated with a transition in ETR-3protein isoforms. We propose that ETR-3 is a major regulator ofcTNT alternative splicing and that the CELF family plays an importantregulatory role in cell-specific alternative splicing during normaldevelopment anddisease.

^* Corresponding author. Mailing address: Department of Pathology, Baylor College of Medicine, Houston, TX 77030. Phone: (713)798-3141. Fax: (713) 798-5838. E-mail: tcooper{at}bcm.tmc.edu.

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