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(Circulation Research. 2008;103:948.)
© 2008 American Heart Association, Inc.

Molecular Medicine

Scleraxis Is Required for Cell Lineage Differentiation and Extracellular Matrix Remodeling During Murine Heart Valve Formation In Vivo

Agata K. Levay, Jacqueline D. Peacock, Yinhui Lu, Manuel Koch, Robert B. Hinton, Jr, Karl E. Kadler, Joy Lincoln

From the Department of Molecular and Cellular Pharmacology (A.K.L., J.D.P., J.L.), Leonard M. Miller School of Medicine, University of Miami, Fla; Wellcome Trust Centre for Cell-Matrix Research (Y.L., K.E.K.), Faculty of Life Sciences, University of Manchester, United Kingdom; Center for Biochemistry (M.K.), Medical Faculty, University of Cologne, Germany; and Division of Cardiology (R.B.H.), Cincinnati Children’s Hospital Medical Center, Ohio.

Correspondence to Joy Lincoln, University of Miami, Molecular and Cellular Pharmacology, Leonard M. Miller School of Medicine, 1600 NW 10th Ave, PO Box 016189 (R-189), RMSB 6048, Miami, FL 33101. E-mail jlincoln{at}med.miami.edu

Heart valve structures, derived from mesenchyme precursor cells, are composed of differentiated cell types and extracellular matrix arranged to facilitate valve function. Scleraxis (scx) is a transcription factor required for tendon cell differentiation and matrix organization. This study identified high levels of scx expression in remodeling heart valve structures at embryonic day 15.5 through postnatal stages using scx-GFP reporter mice and determined the in vivo function using mice null for scx. Scx^–/– mice display significantly thickened heart valve structures from embryonic day 17.5, and valves from mutant mice show alterations in valve precursor cell differentiation and matrix organization. This is indicated by decreased expression of the tendon-related collagen type XIV, increased expression of cartilage-associated genes including sox9, as well as persistent expression of mesenchyme cell markers including msx1 and snai1. In addition, ultrastructure analysis reveals disarray of extracellular matrix and collagen fiber organization within the valve leaflet. Thickened valve structures and increased expression of matrix remodeling genes characteristic of human heart valve disease are observed in juvenile scx^–/– mice. In addition, excessive collagen deposition in annular structures within the atrioventricular junction is observed. Collectively, our studies have identified an in vivo requirement for scx during valvulogenesis and demonstrate its role in cell lineage differentiation and matrix distribution in remodeling valve structures.

Key Words: development • extracellular matrix • heart valves • mouse heart development • transcription factors

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