Wnt signaling in lung organogenesis

Abstract

Reporter transgene, knockout, and misexpression studies support the notion that Wnt/β-catenin signaling regulates aspects of branching morphogenesis, regional specialization of the epithelium and mesenchyme, and establishment of progenitor cell pools. As demonstrated for other foregut endoderm-derived organs, β-catenin and the Wnt/β-catenin signaling pathway contribute to control of cellular proliferation, differentiation and migration. However, the contribution of Wnt/β-catenin signaling to these processes is shaped by other signals impinging on target tissues. In this review, we will concentrate on roles for Wnt/β-catenin in respiratory system development, including segregation of the conducting airway and alveolar compartments, specialization of the mesenchyme, and establishment of tracheal asymmetries and tracheal glands. The Respiratory SystemThe respiratory system is divided into sub-regions that perform specialized functions important for the ultimate goal of delivering oxygen to and removing carbon dioxide from the blood stream. The proximal respiratory system is divided into the nasal and oral cavities and the larynx. The nose and mouth (except in rodents) serve as the primary interface between the respiratory system and the environment, function in humidification of inspired air, and are the first line of defense for protection from injurious agents including pathogens, particles, and chemical or gaseous pollutants. These regions exhibit complex structural and functional characteristics that have been extensively reviewed elsewhere. 1 Little is known of roles for Wnt/ β-catenin signaling in patterning or functional specialization of these tissues. The third component of the proximal respiratory system is the larynx. This region is composed of complex cartilaginous support structures, an epithelial lining, and an extensive muscular and neural network. Although evidence for Wnt/β-catenin signaling during development of this region has been reported 2 high levels of endogenous β-gal activity limit interpretation of studies relying exclusively on LacZ reporter constructs. The larynx is a common target for reconstructive surgery and reparative and signaling mechanisms have been reviewed in the regenerative medicine literature. 3,4 Although the proximal respiratory system plays a critical role in lung diseases that are a direct consequence of environmental exposures as well as those that are exacerbated by environmental triggers, the relative lack of information regarding roles for Wnt/β-catenin in specification and specialization of these prevents further consideration in this review.The distal respiratory system is divided into the conducting airway and alveolar regions. The airway is comprised of a series of dichotomously branched tubes that decrease in caliber from proximal (trachea), through the central airways (bronchi, bronchial and bronchioles) to the distal region (terminal and respiratory bronchioles). In contrast, alveoli are established through post-natal septation of primary sacules. Epithelial ...

Roles for β-Catenin and Doxycycline in the Regulation of Respiratory Epithelial Cell Frequency and Function

“…Studies by several groups established the principle that endoderm specification requires a precise regulation of b-catenin-dependent genes (17,19,20). This principle is consistent with results from other organ systems indicating that too little or too much b-catenin-dependent gene expression altered the specification of cellular fates, phenotypic maturation, and tissue repair, as reviewed by De Langhe and Reynolds (18).…”

“…The WNT/b-catenin signaling pathway is active during endodermal development, and is down-regulated during the pseudoglandularto-alveolar transition (11,(16)(17)(18). Studies by several groups established the principle that endoderm specification requires a precise regulation of b-catenin-dependent genes (17,19,20).…”

β-Catenin in the Alveolar Epithelium Protects from Lung Fibrosis after Intratracheal Bleomycin

“…b-Catenin is a key component to patterning of the alveolar epithelium in lung development (34,35). Overexpression of b-catenin in epithelial cells in the developing lung results in epithelial cell dysplasia and aberrant type II AEC differentiation (6).…”

Wnt3a Mediates the Inhibitory Effect of Hyperoxia on the Transdifferentiation of AECIIs to AECIs

“…Our finding not only supports the previous theory but also reveals the possible pathological mechanisms of hyperoxiainduced lung injury. It needs to be noted that lung branching morphogenesis is regulated by multiple signaling pathways, including the Wnt signaling pathway (De Langhe and Reynolds 2008). β-Catenin is the central signaling mediator of canonical Wnt signaling, which has been found to proximalize the epithelium by expanding the proximal airway and inhibiting distal airway growth (Mucenski et al 2003).…”