title: Foregut separation and tracheo-oesophageal malformations: the role of tracheal outgrowth, dorso-ventral patterning and programmed cell death.
abstract: Foregut division-the separation of dorsal (oesophageal) from ventral (tracheal) foregut components-is a crucial event in gastro-respiratory development, and frequently disturbed in clinical birth defects. Here, we examined three outstanding questions of foregut morphogenesis. The origin of the trachea is suggested to result either from respiratory outgrowth or progressive septation of the foregut tube. We found normal foregut lengthening despite failure of tracheo-oesophageal separation in Adriamycin-treated embryos, whereas active septation was observed only in normal foregut morphogenesis, indicating a primary role for septation. Dorso-ventral patterning of Nkx2.1 (ventral) and Sox2 (dorsal) expression is proposed to be critical for tracheo-oesophageal separation. However, normal dorso-ventral patterning of Nkx2.1 and Sox2 expression occurred in Adriamycin-treated embryos with defective foregut separation. In contrast, Shh expression shifts dynamically, ventral-to-dorsal, solely during normal morphogenesis, particularly implicating Shh in foregut morphogenesis. Dying cells localise to the fusing foregut epithelial ridges, with disturbance of this apoptotic pattern in Adriamycin, Shh and Nkx2.1 models. Strikingly, however, genetic suppression of apoptosis in the Apaf1 mutant did not prevent foregut separation, indicating that apoptosis is not required for tracheo-oesophageal morphogenesis. Epithelial remodelling during septation may cause loss of cell-cell or cell-matrix interactions, resulting in apoptosis (anoikis) as a secondary consequence.
authors.affiliation: Neural Development Unit, UCL Institute of Child Health, London, UK.
authors.forename: Adonis S
authors.initials: AS
authors.lastname: Ioannides
authors.forename: Valentina
authors.initials: V
authors.lastname: Massa
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ferraro
authors.forename: Francesco
authors.initials: F
authors.lastname: Cecconi
authors.forename: Lewis
authors.initials: L
authors.lastname: Spitz
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Henderson
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Copp
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053477:Apoptotic Protease-Activating Factor 1 / Q000235:genetics / Q000378:metabolism; D019521:Body Patterning / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004947:Esophagus / Q000002:abnormalities* / Q000196:embryology* / Q000473:pathology; D005333:Fetus / Q000002:abnormalities / Q000187:drug effects / Q000473:pathology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D053823:Hedgehog Proteins / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D012119:Respiration / Q000187:drug effects; D014132:Trachea / Q000002:abnormalities* / Q000187:drug effects / Q000196:embryology* / Q000473:pathology
chemical_list: C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; D053823:Hedgehog Proteins; C465570:Shh protein, mouse; D004317:Doxorubicin