When a pre-mRNA is first transcribed from a gene, it undergoes extensive processing in the nucleus prior to export to the cytoplasm. 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 such as stress. Mis-regulation of alternative splicing is thought to contribute to several diseases including muscular dystrophy, cancer, and heart disease.
Despite its importance, little is known about the composition and consequences of alternative splicing regulatory programs in the developing heart. My lab uses a combination of molecular, cellular, and whole animal approaches to elucidate the roles of alternative splicing programs regulated by the CUG-BP, Elav-like family (CELF) and muscleblind-like (MBNL) proteins in heart development and function. By using this combinatorial approach, we hope to derive a comprehensive picture of how these important alternative splicing regulatory programs shape heart formation and function at the molecular, cellular, and organismal levels, and gain important new insight into the regulation of critical developmental processes.
A molecular process called alternative splicing allows more than one protein to be made from the same gene. These different proteins may function differently, causing cells that make them to behave differently. Therefore, alternative splicing is highly regulated to prevent the wrong proteins from being made at the wrong time or in the wrong cells. Inappropriate alternative splicing is thought to contribute to several diseases including muscular dystrophy, cancer, and heart disease.
My lab is studying how alternative splicing affects the formation and function of the heart. By understanding how the heart normally forms during development, we hope to gain insight into what causes cardiac birth defects. By understanding how heart muscle function is controlled, we hope to identify ways to improve heart function in patients with heart disease.
Donna Driscoll, Ph.D., Department of Cell Biology, Lerner Research Institute, Cleveland Clinic
Christine Moravec, Ph.D., Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic
Hua Lou, Ph.D., Department of Genetics, Case Western Reserve University
Erik van Lunteren, M.D., Medicine and Neurosciences, Pulmonary Division, Case Western Reserve University and the Cleveland VA Medical Center
Berger, D.S., M. Moyer, G.M. Kliment, E. VanLunteren, A.N. Ladd. 2011. Expression of a dominant negative CELF protein in vivo leads to altered muscle organization, fiber size, and subtype. PLoS ONE. 6(4):e19274.
Terenzi, F. and A.N. Ladd. 2010. Conserved developmental alternative splicing of muscleblind-like (MBNL) transcripts regulates MBNL activity and localization. RNA Biology. 7(1):42-55.
Vajda, N.A., K.R. Brimacombe, K.E. LeMasters, A.N. Ladd. 2009. Muscleblind-like 1 is a negative regulator of TGF-b-dependent epithelial-mesenchymal transition of atrioventricular canal endocardial cells. Dev. Dyn. 238(12):3266-72.
Terenzi, F., K.R. Brimacombe, M.S. Penn, A.N. Ladd. 2009. CELF-mediated alternative splicing is required for cardiac function during early, but not later, postnatal life. J. Mol. Cell. Cardiol. 46:395-404.
Brimacombe, K.R. and A.N. Ladd. 2007. Cloning and embryonic expression patterns of the chicken CELF family. Dev. Dyn. 236(8):2216-24.