Research

The goal of research in our laboratory is to understand the role of pre-mRNA alternative splicing regulatory programs in controlling gene expression and ultimately, cell fate and function, during development.

When a precursor messenger RNA (pre-mRNA) is first transcribed from a gene, it undergoes extensive processing in the nucleus prior to export to the cytoplasm. Introns are removed and exons are pasted together in a process called splicing. The majority of human genes undergo alternative splicing, in which pre-mRNA molecules produced from the same gene are spliced differently to give rise to more than one mature mRNA species. The coding region is often affected, so alternative splicing leads to the production not just of different mRNAs but also different proteins from a single gene. Alternative splicing is highly regulated to prevent the wrong gene products from being produced in the wrong place or at the wrong time. Alternative splicing patterns can be regulated according to cell type, developmental stage, sex, or response to external stimuli. Mis-regulation of alternative splicing is thought to contribute to several diseases including muscular dystrophy and cancer.

Developmentally regulated alternative splicing has been described individually for many genes, yet little is currently known about global changes in alternative splicing that occur during development, to what extent these changes are coordinated, what regulatory factors drive these changes, and most importantly, what the consequences of these changes are for the developing organism. Our laboratory uses a combination of molecular biology and embryology approaches to tackle these questions. The focus of our research is the role of alternative splicing regulatory programs in developing heart and skeletal muscle.

Previous work has identified a family of RNA binding proteins called CUG-BP and ETR-3-like factor (CELF) proteins that regulate pre-mRNA alternative splicing in heart and skeletal muscle. Late embryonic and postnatal changes in CELF protein expression are thought to drive fetal to adult transitions in alternative splicing that are important for maturation of the heart. Disruption of the activity of CELF proteins in the hearts of mice shortly after birth causes heart disease, characterized by molecular changes in alternative splicing as well as cardiac hypertrophy, dilated cardiomyopathy, severe cardiac dysfunction, and premature death. We are now interested in delving into the role of CELF proteins and other splicing regulators in controlling alternative splicing programs that are important for early embryonic heart and muscle development. Our short term goals are: to define the spatial and temporal expression patterns of CELF proteins during embryogenesis, identify additional pre-mRNA targets of CELF regulation, develop alternative splicing profiles in developing striated muscle to elucidate coordinated splicing programs, and test the effects of CELF gene knockdown on alternative splicing and morphogenesis in the heart during early embryogenesis. Our long term goals are: to determine which developmental processes are shaped by alternative splicing regulation, identify the inductive signals that regulate expression and/or intrinsic activity of regulatory splicing factors in striated muscle, and understand how alternative splicing programs are integrated with other regulatory programs during development.