Pre-mRNA alternative splicing is a common means by which cells generate multiple, functionally distinct isoforms from a single gene. Developmentally regulated splicing has been described individually for many genes, yet little is known about how programs of alternative splicing regulation contribute to embryonic development. Members of the CUG-BP and ETR-3-like factor (CELF) and muscleblind-like (MBNL) protein families have been shown to antagonistically regulate pre-mRNA alternative splicing in the heart. We hypothesize that CELF/MBNL-mediated alternative splicing programs play independent as well as overlapping roles in embryonic heart development. We have shown that changes in CELF and MBNL protein expression during cardiac morphogenesis are accompanied by transitions in alternative splicing. Additional preliminary data suggest that the CELF and/or MBNL proteins are critical for normal cardiac morphogenesis and function. The goal of this proposal is to elucidate the roles that CELF/MBNL-mediated alternative splicing programs play during embryonic heart development. We will use chicken and mouse model systems to investigate the effects of disrupting CELF/MBNL-mediated alternative splicing on cardiac morphogenesis and function, and identify the subset of pre-mRNAs subject to CELF/MBNL regulation in the heart. Understanding the roles that CELF/MBNL-mediated splicing programs play in normal embryonic heart development will provide insight into an understudied yet important mechanism of developmentally regulated gene expression. Furthermore, these studies will shed light on how disruption of normal alternative splicing contributes to disease states resulting from developmental perturbation

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Development - 2 Study Section (DEV2)
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Schramm, Charlene A
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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Ladd, A N (2016) New Insights Into the Role of RNA-Binding Proteins in the Regulation of Heart Development. Int Rev Cell Mol Biol 324:125-85
Blech-Hermoni, Yotam; Sullivan, Connor B; Jenkins, Michael W et al. (2016) CUG-BP, Elav-like family member 1 (CELF1) is required for normal myofibrillogenesis, morphogenesis, and contractile function in the embryonic heart. Dev Dyn 245:854-73
Blech-Hermoni, Yotam; Dasgupta, Twishasri; Coram, Ryan J et al. (2016) Identification of Targets of CUG-BP, Elav-Like Family Member 1 (CELF1) Regulation in Embryonic Heart Muscle. PLoS One 11:e0149061
Dasgupta, Twishasri; Coram, Ryan J; Stillwagon, Samantha J et al. (2015) Gene Expression Analyses during Spontaneous Reversal of Cardiomyopathy in Mice with Repressed Nuclear CUG-BP, Elav-Like Family (CELF) Activity in Heart Muscle. PLoS One 10:e0124462
Blech-Hermoni, Yotam; Ladd, Andrea N (2015) Identification of transcripts regulated by CUG-BP, Elav-like family member 1 (CELF1) in primary embryonic cardiomyocytes by RNA-seq. Genom Data 6:74-76
Coram, Ryan J; Stillwagon, Samantha J; Guggilam, Anuradha et al. (2015) Muscleblind-like 1 is required for normal heart valve development in vivo. BMC Dev Biol 15:36
Dasgupta, Twishasri; Stillwagon, Samantha J; Ladd, Andrea N (2013) Gene expression analyses implicate an alternative splicing program in regulating contractile gene expression and serum response factor activity in mice. PLoS One 8:e56590
Ladd, Andrea N (2013) CUG-BP, Elav-like family (CELF)-mediated alternative splicing regulation in the brain during health and disease. Mol Cell Neurosci 56:456-64
Blech-Hermoni, Yotam; Ladd, Andrea N (2013) RNA binding proteins in the regulation of heart development. Int J Biochem Cell Biol 45:2467-78
Blech-Hermoni, Y; Stillwagon, S J; Ladd, A N (2013) Diversity and conservation of CELF1 and CELF2 RNA and protein expression patterns during embryonic development. Dev Dyn 242:767-77

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