Lack of periostin leads to suppression of Notch1 signaling and calcific aortic valve disease.

Abstract

The Postn gene encodes protein periostin. During embryonic development, it is highly expressed in the outflow tract (OFT) endocardial cushions of the developing heart, which give rise to several structures of the mature heart including the aortic valve. Periostin was previously implicated in osteoblast differentiation, cancer metastasis, and tooth and bone development, but its role in cardiac OFT development is unclear. To elucidate the role that periostin plays in the developing heart we analyzed cardiac OFT phenotype in mice after deletion of the Postn gene. We found that lack of periostin in the embryonic OFT leads to ectopic expression of the proosteogenic growth factor pleiotrophin (Ptn) and overexpression of delta-like 1 homolog (Dlk1), a negative regulator of Notch1, in the distal (prevalvular) cushions of the OFT. This resulted in suppression of Notch1 signaling, strong induction of the central transcriptional regulator of osteoblast cell fate Runx2, upregulation of osteopontin and osteocalcin expression, and subsequent calcification of the aortic valve. Our data suggest that periostin represses a default osteogenic program in the OFT cushion mesenchyme and promotes differentiation along a fibrogenic lineage. Lack of periostin causes derepression of the osteogenic potential of OFT mesenchymal cells, calcium deposition, and calcific aortic valve disease. These results establish periostin as a key regulator of OFT endocardial cushion mesenchymal cell fate during embryonic development.

• Authors: Tatiana V Tkatchenko, Ricardo A Moreno-Rodriguez, Simon J Conway, Jeffery D Molkentin, Roger R Markwald, Andrei V Tkatchenko
• Journal: Physiological genomics (Physiol Genomics) Vol. 39 Issue 3 Pg. 160-8 (Nov 06 2009) ISSN: 1531-2267 [Electronic] United States
• PMID: 19723774 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Calcium-Binding Proteins
• Carrier Proteins
• Cell Adhesion Molecules
• Core Binding Factor Alpha 1 Subunit
• Cytokines
• Dlk1 protein, mouse
• Intercellular Signaling Peptides and Proteins
• Notch1 protein, mouse
• Postn protein, mouse
• Receptor, Notch1
• Runx2 protein, mouse
• Spp1 protein, mouse
• Osteopontin
• pleiotrophin

Topics

• Animals
• Aortic Valve (metabolism, pathology)
• Calcinosis
• Calcium-Binding Proteins
• Carrier Proteins (genetics)
• Cell Adhesion Molecules (genetics, physiology)
• Core Binding Factor Alpha 1 Subunit (genetics)
• Cytokines (genetics)
• Echocardiography
• Embryo, Mammalian (embryology, metabolism)
• Gene Expression Profiling
• Gene Expression Regulation, Developmental
• Heart Valve Diseases (genetics, physiopathology)
• In Situ Hybridization, Fluorescence
• Intercellular Signaling Peptides and Proteins (genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myocardium (metabolism, pathology)
• Osteopontin (genetics)
• Receptor, Notch1 (genetics, physiology)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (genetics, physiology)
• Time Factors