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.

Sonic Hedgehog Signaling and VACTERL Association

“…Dynamic ventral-dorsal shift in Shh signaling is required for the onset of tracheo-esophageal separation and foregut morphogenesis. Spatio-temporal disruption or shift of Shh expression is frequently associated with diminished apoptosis of the lateral epithelial ridges and the failure of tracheo-esophageal separation [Ioannides et al, 2010]. In absence of Shh, mice display a spectrum of foregut malformations, including lung hypoplasia and various defects in the trachea and esophagus.…”

The building blocks of mammalian lung development

“…The trachea and lung both arise from an Nkx2-1 þ region of the foregut and presumably from a common progenitor population (reviewed in Cardoso and Lu, 2006). However, the trachea does not undergo branching morphogenesis, rather it separates from the future esophagus by means of a process of septation (Ioannides et al, 2010). Indeed after the initial specification of the Nkx2-1 þ anterior foregut domain, the lung and trachea have somewhat different patterns of gene expression.…”

Sox2 Activates Cell Proliferation and Differentiation in the Respiratory Epithelium

“…In mice, Sox2 is required for normal morphogenesis and homeostasis of diverse tissues, including neural stem cells; retinal stem cells taste buds; hair sensory follicles in the ear; and epithelia of trachea, lung, and esophagus (15)(16)(17)(18). In humans, Sox2 mutations are associated with eye and tracheal/esophageal malformations (18)(19)(20). Recent studies demonstrated that Sox2 is amplified in human lung and esophageal squamous cell carcinomas (21)(22)(23).…”