Abstract

The lungs are divided, both structurally and functionally, into two distinct components, the proximal airways, which conduct air, and the peripheral airways, which mediate gas exchange. The mechanisms that control the specification of these two structures during lung development are currently unknown. Here we show that beta-catenin signaling is required for the formation of the distal, but not the proximal, airways. When the gene for beta-catenin was conditionally excised in epithelial cells of the developing mouse lung prior to embryonic day 14.5, the proximal lung tubules grew and differentiated appropriately. The mice, however, died at birth because of respiratory failure. Analysis of the lungs by in situ hybridization and immunohistochemistry, using molecular markers of the epithelial and mesenchymal components of both proximal and peripheral airways, showed that the lungs were composed primarily of proximal airways. These observations establish, for the first time, both the sites and timing of specification of the proximal and peripheral airways in the developing lung, and that beta-catenin is one of the essential components of this specification.

Highlights

  • The lungs are divided, both structurally and functionally, into two distinct components, the proximal airways, which conduct air, and the peripheral airways, which mediate gas exchange

  • During the canalicular and saccular stages of lung development (E16.5 to E17.5 and E17.5 to postnatal day 4, respectively), the acinar tubules dilate into terminal alveolar saccules and the mesenchyme thins in association with formation of an extensive capillary network, forming the gas exchange region required for respiration after birth [1]

  • Numerous signaling and transcriptional pathways, including those associated with fibroblast growth factors (Fgfs), sonic hedgehog (Shh), bone morphogenetic protein 4 (Bmp4), vascular endothelial growth factors (Vegfs), thyroid transcription factor 1 (Titf1), and Wnts have been implicated in these interactions during lung morphogenesis [2,3,4,5,6,7,8,9,10]

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Summary

The abbreviations used are

E, embryonic; Fgf, fibroblast growth factor; Shh, sonic hedgehog; Bmp, bone morphogenetic protein 4; Vegf, vascular endothelial growth factor; Titf and TTF-1, thyroid transcription factor 1 gene and protein, respectively; TCF, T cell factor; LEF, lymphoid enhancer factor; Fzd, Frizzled; CRE, Cre recombinase; SP-C, surfactant protein C; CCSP, Clara cell secretory protein; rtTA, reverse tetracycline transactivator; ϩ, wild-type; tg, transgene; flx, floxed; PECAM, platelet endothelial cell adhesion molecule; ␣-SMA, ␣-smooth muscle actin; BrdUrd, 5-bromo-2Ј-deoxyuridine and 5-fluoro-2Ј-deoxyuridine (10:1); SP-A, surfactant protein A; SP-B, surfactant protein B; lox, loxP; FgfR2IIIb, fibroblast growth factor receptor 2IIIb. The WNT/␤-catenin signal transduction pathway controls a variety of biological processes, including embryonic patterning, development of the nervous system, and stem cell proliferation in Drosophila (reviewed in Ref. 13), as well as dorsal mesoderm induction and axis specification in Xenopus [14]. Hypophosphorylated ␤-catenin accumulates in the cytoplasm, is translocated to the nucleus, and interacts with members of the TCF/LEF transcription factor family to become components of a transcription complex that regulates the expression of downstream target genes A number of WNT ligands, Fzd receptors, and TCF/LEF proteins have been detected in lung tissue during embryonic development [17,18,19,20,21], the potential role of ␤-catenin in lung morphogenesis has not been determined. Because deletion of ␤-catenin is lethal before the initiation of lung development in the mouse embryo, a doxycycline-induced, Cre recombinase (CRE)-mediated, homologous recombination strategy was utilized to eliminate ␤-catenin expression in epithelial cells of the embryonic mouse lung

EXPERIMENTAL PROCEDURES
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DISCUSSION

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