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

Abstract

Abstract-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 Ϫ/Ϫ 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 cartilageassociated 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 Ϫ/Ϫ 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. (Circ Res. 2008;103:948-956.)

TGFβ1regulates Scleraxis expression in primary cardiac myofibroblasts by a Smad-independent mechanism

“…MAPK REGULATION OF SCLERAXIS valvular interstitial cells of myxomatous valves in samples obtained from human patients and developmental murine models (3,25). However, to date, none of these studies have examined the direct DNA/protein interaction with respect to whether Smad signaling (or Smad-independent signaling) is driving TGF␤ 1 -induced Scleraxis expression in primary rat myofibroblasts.…”

Signaling and Transcriptional Networks in Heart Development and Regeneration

“…For example, calcineurin/ NFAT signaling in the endocardium is deployed again, following its initial function in the myocardium (Chang et al 2004). Although less well understood than the early stages of valvulogenesis, maturation of valves involves profound changes in gene expression and cellular identity, with the loss of early markers such as Twist1 and Tbx20, and the acquisition of a tendonlike phenotype, with expression of Sox9 and Scleraxis (Lincoln et al 2007;Levay et al 2008). …”

Genomic characterization of Wilms' tumor suppressor 1 targets in nephron progenitor cells during kidney development

“…Related Pbx1 regulates ureteric bud branching (Schnabel et al, 2003) Plxdc2 10.03 <0.001 Potential Semaphorin growth factor receptor in neural development (Miller et al, 2007) 11.9 <0.001 Neurite differentiation (Fischer et al, 2009) Rps6ka3 Fgfr3-dependent hematopoietic transformation (Kang et al, 2007;Kang et al, 2009) 14.68 <0.001 Tendon development (Brent et al, 2004;Edom-Vovard et al, 2002) Heart valve development (Levay et al, 2008) …”