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Andrea N. Ladd, Ph.D.Assistant StaffDepartment of Cell Biology |
Area of general research interest:
Pre-mRNA alternative splicing regulation in vertebrate heart and muscle development
Current program:
- Investigating pre-mRNA alternative splicing programs during heart and muscle development
- Using chick embryos to explore the role of alternative splicing programs during cardiac morphogenesis
- Using transgenic mouse models to investigate the role of CELF proteins in heart and skeletal muscle
Investigators:
- Fulvia Terenzi, Ph.D., Research Associate
- Natalie Vajda, B.S., Research Technician
Lab Alumni:
- Sam Chai, Undergraduate Student, Summers 2005 and 2006
- Tony Macedonia, Undergraduate Student, Summer 2006
- Satoko Kanahara, B.A., CCLCM Student, Summer 2006
- Kyle Brimacombe, B.A., Research Technician, 2005-2007
- Dara Berger, Ph.D., Postdoctoral Fellow, 2006-2008
- Kimberly Hung, B.S., CCLCM Student, Summer 2008
Collaborators:
- Marc Penn, M.D., Ph.D., Department of Cell Biology, CCF
- Donna Driscoll, Ph.D., Department of Cell Biology, CCF
- Hua Lou, Ph.D., Department of Genetics, Case Western Reserve University
- Erik van Lunteren, M.D., Department of Medicine, Case Western Reserve University
Brief description:
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 demonstrated that two families of RNA binding proteins, the CUG-BP and ETR-3-like factor (CELF) family and the muscleblind-like (MBNL) family, antagonistically regulate conserved transitions in pre-mRNA alternative splicing during heart and skeletal muscle development. We use a combination of molecular and embryological approaches to investigate the roles of CELF- and MBNL-mediated alternative splicing programs in embryonic and postnatal heart and muscle development.
Key references:
Brimacombe, K.R. and A.N. Ladd. 2007. Cloning and embryonic expression patterns of the chicken CELF family. Dev. Dyn. In press.
Ladd, A.N., G. Taffet, C. Hartley, D. Kearney, and T.A. Cooper. 2005. Cardiac-specific repression of CELF activity disrupts alternative splicing and causes cardiomyopathy. Mol. Cell. Biol. 25: 6267-6278.
Ladd, A.N., M.G. Stenberg, M.S. Swanson, and T.A. Cooper. 2005. A dynamic balance between activation and repression regulates pre-mRNA alternative splicing during heart development. Dev. Dyn. 233(3): 783-793.
Ladd, A.N. and T.A. Cooper. 2004. Multiple domains control the subcellular localization and activity of ETR-3, a regulator of nuclear and cytoplasmic RNA processing events. J. Cell Sci. 117(16): 3519-3529.
Ladd, A.N., N.H. Nguyen, K. Malhotra, and T.A. Cooper. 2004. CELF6, a Member of the CELF Family of RNA Binding Proteins, Regulates Muscle-specific Splicing Enhancer-dependent Alternative Splicing. J. Biol. Chem. 279(17): 17756-17764.
Ladd, A.N., and T.A. Cooper. 2002. Finding Signals that Regulate Alternative Splicing in the Post-Genomic Era. Genome Biol. 3(11): reviews0008.1-0008.16.
Ladd, A.N., N. Charlet-B., and T.A. Cooper. 2001. The CELF family of RNA binding proteins is implicated in cell-specific and developmentally regulated alternative splicing. Mol. Cell. Biol. 21(4): 1285-1296.