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First published online April 12, 2006
doi: 10.1242/10.1242/dev.02310

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Regulation of early lung morphogenesis: questions, facts and controversies

Pulmonary Center, Boston University School of Medicine, Boston, MA 02118, USA

View larger version (37K): [in a new window]   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.

View larger version (35K): [in a new window]   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).

View larger version (47K): [in a new window]   Fig. 3. Models of bud formation and proximodistal patterning in the developing lung. A developing lung bud during branching morphogenesis. Mesenchyme is depicted in gray and the epithelium in blue or red (distal bud). (A) Branching initiates with local Fgf10 expression in the distal mesenchyme. Fgf10 diffuses (yellow arrow) and binds locally to Fgfr2b (expressed throughout the lung epithelium) to activate signaling and induce a bud (white arrow). (B) As the bud elongates, Fgfr2b signaling induces expression of Spry2 (which negatively regulates Fgf signaling and inhibits budding, broken yellow line) and Bmp4 in the distal epithelium. Bmp4 possibly also inhibits distal budding through autocrine signaling from the epithelium (Eblaghie et al., 2006) (broken yellow line) and can also enhance budding in a paracrine fashion (broken yellow arrow), via an unidentified mesenchymal signal (X). Mesenchymal Pod1 (Tcf21) (indirectly) and epithelial Wnt signaling regulate Bmp4 (see F). Mechanisms that might inhibit ectopic budding in stalk regions include: netrin-mediated Fgfr2b signaling inhibition (broken yellow line); Tgfb activation in the epithelium by Tgfb1 from the subepithelial mesenchyme; Tgfb1-induced synthesis of extracellular matrix (ECM) components, such as collagen and fibronectin, and Tgfbi in stalk mesenchyme. (C) Control of Fgf10 and Fgfr2b expression. Canonical Wnt signaling activates Fgfr2b expression in the lung epithelium; mesenchymal Wnt (alone or with epithelial Wnt) inhibits Fgf10. Positive regulators of Fgf10 include Foxf1, Tbx4 and Tbx5. Tgfb1 signaling in stalk mesenchyme may prevent Fgf10 expression in the proximal mesenchyme (box in C). Shh signaling in the distal mesenchyme inhibits Fgf10 expression, but via Gli3 also controls availability of Foxf1, a positive regulator of Fgf10. Shh induction of Hhip expression inhibits Shh signaling (broken yellow line) to allow Fgf10 expression. (D) At the bud tips, high Shh (distal epithelium) and Hhip (distal mesenchyme) levels result in overall less Shh signaling and more Fgf10 than in the immediately adjacent regions, where Shh signaling is unopposed by Hhip. Low Shh levels in more proximal bud regions allow Fgf10 expression in the adjacent mesenchyme, resulting in later induction of lateral buds. (E) The proliferation of multipotent mesenchymal progenitors while the lung grows depends on Shh and Wnt7b signals from the distal epithelium and on Fgf9 from the pleura (purple). Foxa1 and Foxa2 regulate Shh and Wnt7b expression. Vegf regulates endothelial cell differentiation. RA (from the pleura) may regulate Fgf9 expression but this remains to be shown. (F) A model of proximodistal cell fate regulation in the lung bud epithelium. Mycn and Fgf10 (via Fgfr2b epithelial signaling) maintain the proliferation of progenitor cells of the distal lung epithelium. Bmp4 prevents distal epithelial cells from assuming a proximal phenotype. Wnt signaling regulates the timing of their differentiation (presumably by controlling Bmp4 and Mycn expression) and is negatively regulated by dickkopf 1 (Dkk1). Foxj1 induces differentiation of proximal epithelium into ciliated cells. See text for references and Eblaghie et al. (Eblaghie et al., 2006).