title: Semaphorin 3d signaling defects are associated with anomalous pulmonary venous connections.
abstract: Total anomalous pulmonary venous connection (TAPVC) is a potentially lethal congenital disorder that occurs when the pulmonary veins do not connect normally to the left atrium, allowing mixing of pulmonary and systemic blood. In contrast to the extensive knowledge of arterial vascular patterning, little is known about the patterning of veins. Here we show that the secreted guidance molecule semaphorin 3d (Sema3d) is crucial for the normal patterning of pulmonary veins. Prevailing models suggest that TAPVC occurs when the midpharyngeal endothelial strand (MES), the precursor of the common pulmonary vein, does not form at the proper location on the dorsal surface of the embryonic common atrium. However, we found that TAPVC occurs in Sema3d mutant mice despite normal formation of the MES. In these embryos, the maturing pulmonary venous plexus does not anastomose uniquely with the properly formed MES. In the absence of Sema3d, endothelial tubes form in a region that is normally avascular, resulting in aberrant connections. Normally, Sema3d provides a repulsive cue to endothelial cells in this area, establishing a boundary. Sequencing of SEMA3D in individuals with anomalous pulmonary veins identified a phenylalanine-to-leucine substitution that adversely affects SEMA3D function. These results identify Sema3d as a crucial pulmonary venous patterning cue and provide experimental evidence for an alternate developmental model to explain abnormal pulmonary venous connections.
authors.affiliation: Department of Pediatrics, Division of Cardiology, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Degenhardt
authors.forename: Manvendra K
authors.initials: MK
authors.lastname: Singh
authors.forename: Haig
authors.initials: H
authors.lastname: Aghajanian
authors.forename: Daniele
authors.initials: D
authors.lastname: Massera
authors.forename: Qiaohong
authors.initials: Q
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Connie
authors.initials: C
authors.lastname: Choi
authors.forename: Amanda D
authors.initials: AD
authors.lastname: Yzaguirre
authors.forename: Lauren J
authors.initials: LJ
authors.lastname: Francey
authors.forename: Emily
authors.initials: E
authors.lastname: Gallant
authors.forename: Ian D
authors.initials: ID
authors.lastname: Krantz
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Gruber
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Epstein
mesh_terms: D000818:Animals; D042783:Endothelial Cells / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009363:Neoplasm Proteins / Q000502:physiology; D039942:Neuropilin-1 / Q000032:analysis; D011667:Pulmonary Veins / Q000002:abnormalities* / Q000196:embryology; D039961:Semaphorins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D009363:Neoplasm Proteins; C530499:Sema 3D protein, mouse; D039961:Semaphorins; C079844:beta-chimaerin; D039942:Neuropilin-1