Fig. 1. Key events during early development of the mouse respiratory system. (A) The foregut (gray tube) is initially specified into organ-specific domains along its anteroposterior (AP) axis, which later give rise to the thyroid (Th), thymus, trachea (Tr), lung (Lu), liver (Li) and pancreas (Pa). The respiratory progenitors (Tr, Lu) arise from the ventral foregut endoderm, which is posterior to the thyroid but anterior to the liver and to the pancreatic fields. Lung and tracheal progenitors are identified collectively at E9.0 by Nkx2.1 expression (purple), which also labels the thyroid. (B) At E9.5, two endodermal lung buds (black arrows) are induced from the ventral-lateral aspect of the foregut, which then invade the adjacent mesoderm and elongate to form the primary buds (red arrows) of the right and left lung (V-D, ventral-dorsal axis). (C) With primary lung bud formation, the tracheal (Tr) primordium forms ventrally and separates from the dorsal foregut, the primitive esophagus (Es), in a poorly understood process that is possibly initiated by growth of an ascending tracheoesophageal septum or by fusion of endodermal ridges from the lateral walls of the foregut (Zaw-Tun, 1982; Sutliff and Hutchins, 1994; Ioannides et al., 2002). (D) At E10.5 (left), secondary buds arise as outgrowths from the primary lung buds at specific positions (red arrowheads; the epithelium is labeled by Fgfr2b). In the right lung (RLu), these buds later develop into separate lobes. At E11.5-12.0 (right), the left lung (LLu) has one lobe and RLu has four: the cranial (cr), medial (me), caudal (ca) and accessory (ac) lobes. From E10.5 to E16.5-E17.0, the epithelium undergoes branching morphogenesis, which involves bud outgrowth and elongation, dichotomous subdivisions and cleft formation at branching points. The process is reiterated over several generations of branches to form the respiratory (bronchial) tree. As this occurs, a proximodistal axis is established in the developing lung. Proximal regions (where buds are initially generated, yellow) stop branching and differentiate into proximal airways (bronchi), while distal regions (green) continue to branch and later give rise to the alveolar region of the lung. Numbers depict primary, secondary and tertiary generations of buds.