Fig. 2. Molecular regulation of initial events in lung and tracheal development. (A) The developing mouse foregut from embryonic day (E) 8.0 to E9.0. (a) The Foxa and Gata transcription factors genes (yellow) are involved in early events, such as foregut (Fg) tube closure and establishing endodermal competence. (b,c) A model of foregut specification, in which increasing thresholds of Fgfs (purple), emanating from the heart (Ht), specify the ventral foregut endoderm into liver (Li) (blue line) or into lung (Lu) and thyroid (Th) (red, Nkx2.1-expressing endoderm). [See text and Serls et al. (Serls et al., 2005) for details.] (B) Regulation of primary lung bud formation, based on data from mouse and chick (see text for details). Foregut mesoderm is shown in gray, endoderm in blue, and the endoderm of the prospective trachea and lung in red. Lung budding (red) results from mesodermal induction of Fgf10 and from activation of Fgfr2b signaling in the endoderm (indicated by a yellow bracket). Retinoic acid (RA) and Tbx genes (TBX4 in chicks) regulate Fgf10 expression. Gli2 and Gli3 are both required for primary lung bud formation, presumably via an unknown intermediate factor (X). Bmp4 is expressed in the ventral mesoderm at the lung field, where its role is unknown. (C) Trachea (Tr) formation from the ventral foregut and its separation from the dorsal gut tube (Es, primitive esophagus). A cross-section through the foregut shows dorsoventral (DV) differences in gene expression that probably influence this process. For example, mice deficient in Shh or Nkx2.1, which are normally present in the ventral foregut endoderm, show tracheoesophageal fistula (incomplete separation of the respiratory and digestive systems) (Minoo et al., 1999; Litingtung et al., 1998). This defect has been also associated with deficiencies in Foxf1 (Lim et al., 2002), Tbx4 (Sakiyama et al., 2003) and RA (Dickman et al., 1997).