title: Mesenchymal adenomatous polyposis coli plays critical and diverse roles in regulating lung development.
abstract: BACKGROUND
  Adenomatous polyposis coli (Apc) is a tumor suppressor that inhibits Wnt/Ctnnb1. Mutations of Apc will not only lead to familial adenomatous polyposis with associated epithelial lesions, but will also cause aggressive fibromatosis in mesenchymal cells. However, the roles of Apc in regulating mesenchymal cell biology and organogenesis during development are unknown.
  
  
  RESULTS
  We have specifically deleted the Apc gene in lung mesenchymal cells during early lung development in mice. Loss of Apc function resulted in immediate mesenchymal cell hyperproliferation through abnormal activation of Wnt/Ctnnb1, followed by a subsequent inhibition of cell proliferation due to cell cycle arrest at G0/G1, which was caused by a mechanism independent of Wnt/Ctnnb1. Meanwhile, abrogation of Apc also disrupted lung mesenchymal cell differentiation, including decreased airway and vascular smooth muscle cells, the presence of Sox9-positive mesenchymal cells in the peripheral lung, and excessive versican production. Moreover, lung epithelial branching morphogenesis was drastically inhibited due to disrupted Bmp4-Fgf10 morphogen production and regulation in surrounding lung mesenchyme. Lastly, lung mesenchyme-specific Apc conditional knockout also resulted in altered lung vasculogenesis and disrupted pulmonary vascular continuity through a paracrine mechanism, leading to massive pulmonary hemorrhage and lethality at mid-gestation when the pulmonary circulation should have started.
  
  
  CONCLUSIONS
  Our study suggests that Apc in lung mesenchyme plays central roles in coordinating the proper development of several quite different cellular compartments including lung epithelial branching and pulmonary vascular circulation during lung organogenesis.
authors.affiliation: Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, 90027, USA.|Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90027, USA.
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, Justus Liebig University Giessen, 35392, Giessen, Hessen, Germany.
authors.forename: Elie
authors.initials: E
authors.lastname: El Agha
authors.affiliation: Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, 90027, USA.|Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90027, USA.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Turcatel
authors.affiliation: Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, 90027, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, 90027, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Chiu
authors.affiliation: Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, 90027, USA.|Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90027, USA.
authors.forename: David
authors.initials: D
authors.lastname: Warburton
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, Justus Liebig University Giessen, 35392, Giessen, Hessen, Germany.|Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008, Kazan, Russian Federation.
authors.forename: Saverio
authors.initials: S
authors.lastname: Bellusci
authors.affiliation: Spine Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China.
authors.forename: Bang-Ping
authors.initials: BP
authors.lastname: Qian
authors.affiliation: Department of Genetics, University of Georgia, Athens, GA, 30602, USA.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Menke
authors.affiliation: Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, 90027, USA. wshi@chla.usc.edu.|Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90027, USA. wshi@chla.usc.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000818:Animals; D002454:Cell Differentiation; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D008168:Lung / Q000002:abnormalities* / Q000098:blood supply / Q000254:growth & development* / Q000378:metabolism; D008648:Mesoderm / Q000002:abnormalities / Q000166:cytology* / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C495267:CTNNB1 protein, mouse; D051153:Wnt Proteins; D051176:beta Catenin