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PMID:18802027

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Citation

Levay, AK, Peacock, JD, Lu, Y, Koch, M, Hinton, RB Jr, Kadler, KE and Lincoln, J (2008) Scleraxis is required for cell lineage differentiation and extracellular matrix remodeling during murine heart valve formation in vivo. Circ. Res. 103:948-56

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(-/-) 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.

Links

PubMed PMC2743952 Online version:10.1161/CIRCRESAHA.108.177238

Keywords

Aging; Animals; Basic Helix-Loop-Helix Transcription Factors/deficiency; Basic Helix-Loop-Helix Transcription Factors/genetics; Basic Helix-Loop-Helix Transcription Factors/metabolism; Cartilage/embryology; Cartilage/metabolism; Cell Differentiation/genetics; Cell Lineage/genetics; Collagen/metabolism; Extracellular Matrix/genetics; Extracellular Matrix/metabolism; Extracellular Matrix/ultrastructure; Fibrosis; Gene Expression Regulation, Developmental; Gestational Age; Glycoproteins/metabolism; Green Fluorescent Proteins/metabolism; Heart Valve Diseases/embryology; Heart Valve Diseases/metabolism; Heart Valves/embryology; Heart Valves/growth & development; Heart Valves/metabolism; Heart Valves/ultrastructure; Mesoderm/metabolism; Mice; Mice, Knockout; Organogenesis/genetics; Recombinant Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:SCX

involved_in

GO:0030199: collagen fibril organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SCX

involved_in

GO:0030154: cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SCX

involved_in

GO:0001894: tissue homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(UBERON:0002384)

Seeded From UniProt

complete

MOUSE:SCX

involved_in

GO:0032967: positive regulation of collagen biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SCX

involved_in

GO:0010628: positive regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SCX

involved_in

GO:0003188: heart valve formation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SCX

involved_in

GO:0003179: heart valve morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SCX

involved_in

GO:0061035: regulation of cartilage development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SCX

involved_in

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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