Role of pre-mRNA alternative splicing programs in heart and muscle development

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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