title: Alk3 mediated Bmp signaling controls the contribution of epicardially derived cells to the tissues of the atrioventricular junction.
abstract: Recent studies using mouse models for cell fate tracing of epicardial derived cells (EPDCs) have demonstrated that at the atrioventricular (AV) junction EPDCs contribute to the mesenchyme of the AV sulcus, the annulus fibrosus, and the parietal leaflets of the AV valves. There is little insight, however, into the mechanisms that govern the contribution of EPDCs to these tissues. While it has been demonstrated that bone morphogenetic protein (Bmp) signaling is required for AV cushion formation, its role in regulating EPDC contribution to the AV junction remains unexplored. To determine the role of Bmp signaling in the contribution of EPDCs to the AV junction, the Bmp receptor activin-like kinase 3 (Alk3; or Bmpr1a) was conditionally deleted in the epicardium and EPDCs using the mWt1/IRES/GFP-Cre (Wt1(Cre)) mouse. Embryonic Wt1(Cre);Alk3(fl/fl) specimens showed a significantly smaller AV sulcus and a severely underdeveloped annulus fibrosus. Electrophysiological analysis of adult Wt1(Cre);Alk3(fl/fl) mice showed, unexpectedly, no ventricular pre-excitation. Cell fate tracing revealed a significant decrease in the number of EPDCs within the parietal leaflets of the AV valves. Postnatal Wt1(Cre);Alk3(fl/fl) specimens showed myxomatous changes in the leaflets of the mitral valve. Together these observations indicate that Alk3 mediated Bmp signaling is important in the cascade of events that regulate the contribution of EPDCs to the AV sulcus, annulus fibrosus, and the parietal leaflets of the AV valves. Furthermore, this study shows that EPDCs do not only play a critical role in early developmental events at the AV junction, but that they also are important in the normal maturation of the AV valves.
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Marie M
authors.initials: MM
authors.lastname: Lockhart
authors.affiliation: Department of Biomedical Engineering, Washington University, St. Louis, MO, USA.
authors.forename: Bastiaan J D
authors.initials: BJ
authors.lastname: Boukens
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Aimee L
authors.initials: AL
authors.lastname: Phelps
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Christina-Lin M
authors.initials: CL
authors.lastname: Brown
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Katelynn A
authors.initials: KA
authors.lastname: Toomer
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Tara A
authors.initials: TA
authors.lastname: Burns
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery and Pediatrics, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Rupak D
authors.initials: RD
authors.lastname: Mukherjee
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Russell A
authors.initials: RA
authors.lastname: Norris
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Trusk
authors.affiliation: Heart Failure Research Center, Department of Anatomy, Embryology and Physiology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Maurice J B
authors.initials: MJ
authors.lastname: van den Hoff
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA. Electronic address: wesselsa@musc.edu.
authors.forename: Andy
authors.initials: A
authors.lastname: Wessels
mesh_terms: D000818:Animals; D017209:Apoptosis; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000502:physiology*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D019070:Cell Lineage; D002465:Cell Movement; D049109:Cell Proliferation; D003433:Crosses, Genetic; D004562:Electrocardiography; D004594:Electrophysiology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006325:Heart Atria / Q000196:embryology*; D006352:Heart Ventricles / Q000196:embryology*; D021621:Imaging, Three-Dimensional; D008297:Male; D051379:Mice; D008943:Mitral Valve / Q000196:embryology; D010496:Pericardium / Q000166:cytology / Q000196:embryology*; D010641:Phenotype; D015398:Signal Transduction
chemical_list: D019485:Bone Morphogenetic Proteins; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I
keywords: Bone morphogenetic protein; Development; Epicardium; Myxomatous; Valves