Poster abstracts
Poster number 29 submitted by Ryan Coram
Muscleblind-like 1 regulates alternative splicing and transforming growth factor beta signaling during heart valve development
Ryan J. Coram (Department of Cellular & Molecular Medicine, Cleveland Clinic), Samantha S. Stillwagon (Department of Cellular & Molecular Medicine, Cleveland Clinic), Anuradha Guggilam (Department of Cellular & Molecular Medicine, Cleveland Clinic), Stanley L. Hazen (Department of Cellular & Molecular Medicine, Cleveland Clinic), Maurice S. Swanson (Department of Molecular Genetics & Microbiology, University of Florida, Gainesville), Andrea N. Ladd (Department of Cellular & Molecular Medicine, Cleveland Clinic)
Abstract:
Approximately 5% of infants are born with heart defects, among the most common of which are valve defects. The heart valves develop through the formation and remodeling of endocardial cushions in the atrioventricular canal (AVC) and outflow tract (OFT). A subpopulation of endocardial cells undergoes an epithelial-mesenchymal transition (EMT) to give rise to invasive mesenchyme, which later differentiates into fibroblasts that establish and maintain the stratified matrix of the mature heart valves. Endocardial cushion EMT is induced by transforming growth factor beta (TGFb). TGFb signaling has also been linked with post-EMT cushion remodeling and valve maintenance, but little is known about how TGFb signaling is regulated. Muscleblind-like 1 (MBNL1) is a highly conserved RNA binding protein. We previously demonstrated that in the chick, MBNL1 is highly expressed in AVC and OFT endocardium, and knockdown of MBNL1 promotes TGFb signaling and invasive mesenchyme production. As in the chick, we found that MBNL1 is highly expressed in AVC and OFT endocardium and mesenchyme in the mouse embryo. Loss of MBNL1 enhances EMT ex vivo in mouse endocardial cushion explants, and induces precocious EMT in vivo in Mbnl1-null mice. MBNL1 expression continues in post-EMT cushions and adult heart valves, and adult Mbnl1-null mice exhibit valve dysmorphia and dysfunction, enhanced TGFb signaling, and altered extracellular matrix composition. Regulation of TGFb activity has been linked to alternative splicing of a MBNL1 target, fibronectin (Fn), a matrix protein with critical roles in cell adhesion and migration. We have found that MBNL1-dependent Fn alternative splicing changes correlate with changes in TGFb and mesenchymal markers in a murine cell culture model of TGFb-dependent EMT. Together, these data indicate that MBNL1 plays a conserved role as a regulator of TGFb signaling, EMT, and valvulogenesis during heart development.
Keywords: MBNL1, EMT, heart development