RATIONALE: In early heart development, platelet-derived growth factor (PDGF) receptor expression in the heart ventricles is restricted to the epicardium. Previously, we showed that PDGFRβ is required for coronary vascular smooth muscle cell (cVSMC) development, but a role for PDGFRα has not been identified. Therefore, we investigated the combined and independent roles of these receptors in epicardial development. OBJECTIVE: To understand the contribution of PDGF receptors in epicardial development and epicardial-derived cell fate determination. METHODS AND RESULTS: By generating mice with epicardial-specific deletion of the PDGF receptors, we found that epicardial epithelial-to-mesenchymal transition (EMT) was defective. Sox9, an SRY-related transcription factor, was reduced in PDGF receptor-deficient epicardial cells, and overexpression of Sox9 restored epicardial migration, actin reorganization, and EMT gene expression profiles. The failure of epicardial EMT resulted in hearts that lacked epicardial-derived cardiac fibroblasts and cVSMC. Loss of PDGFRα resulted in a specific disruption of cardiac fibroblast development, whereas cVSMC development was unperturbed. CONCLUSIONS: Signaling through both PDGF receptors is necessary for epicardial EMT and formation of epicardial-mesenchymal derivatives. PDGF receptors also have independent functions in the development of specific epicardial-derived cell fates.
RATIONALE: In early heart development, platelet-derived growth factor (PDGF) receptor expression in the heart ventricles is restricted to the epicardium. Previously, we showed that PDGFRβ is required for coronary vascular smooth muscle cell (cVSMC) development, but a role for PDGFRα has not been identified. Therefore, we investigated the combined and independent roles of these receptors in epicardial development. OBJECTIVE: To understand the contribution of PDGF receptors in epicardial development and epicardial-derived cell fate determination. METHODS AND RESULTS: By generating mice with epicardial-specific deletion of the PDGF receptors, we found that epicardial epithelial-to-mesenchymal transition (EMT) was defective. Sox9, an SRY-related transcription factor, was reduced in PDGF receptor-deficient epicardial cells, and overexpression of Sox9 restored epicardial migration, actin reorganization, and EMT gene expression profiles. The failure of epicardial EMT resulted in hearts that lacked epicardial-derived cardiac fibroblasts and cVSMC. Loss of PDGFRα resulted in a specific disruption of cardiac fibroblast development, whereas cVSMC development was unperturbed. CONCLUSIONS: Signaling through both PDGF receptors is necessary for epicardial EMT and formation of epicardial-mesenchymal derivatives. PDGF receptors also have independent functions in the development of specific epicardial-derived cell fates.
Authors: Haruhiko Akiyama; Marie-Christine Chaboissier; Richard R Behringer; David H Rowitch; Andreas Schedl; Jonathan A Epstein; Benoit de Crombrugghe Journal: Proc Natl Acad Sci U S A Date: 2004-04-19 Impact factor: 11.205
Authors: J M Veltmaat; C C Orelio; D Ward-Van Oostwaard; M A Van Rooijen; C L Mummery; L H Defize Journal: Int J Dev Biol Date: 2000-04 Impact factor: 2.203
Authors: Elisabeth M Zeisberg; Oleg Tarnavski; Michael Zeisberg; Adam L Dorfman; Julie R McMullen; Erika Gustafsson; Anil Chandraker; Xueli Yuan; William T Pu; Anita B Roberts; Eric G Neilson; Mohamed H Sayegh; Seigo Izumo; Raghu Kalluri Journal: Nat Med Date: 2007-07-29 Impact factor: 53.440
Authors: Xi-Song Ke; Yi Qu; Naomi Goldfinger; Kari Rostad; Randi Hovland; Lars A Akslen; Varda Rotter; Anne Margrete Øyan; Karl-Henning Kalland Journal: PLoS One Date: 2008-10-13 Impact factor: 3.240