The lung develops through a series of endoderm-mesoderm interactions that promote proper patterning of the highly complex and arborized structure required for postnatal respiration. Little is understood about how Wnt signaling promotes these early stages of lung development, whether Wnt signaling regulates specific aspects of early branching morphogenesis of the airway and vascular structures in the lung, and whether disruption of Wnt signaling can lead to human lung disease. Our preliminary data show that Wnt signaling regulates a specific type of airway branching called domain branching through the receptor Fzd2 and that disruption of domain branching leads to a phenotype resembling congenital cystic adenomatoid malformation (CCAM) in pediatric patients. Moreover, the molecular alterations that occur upon loss of Fzd2, including increased Fgf9 expression and decreased Fgf7 expression, also mimic the CCAM phenotype. Using a novel inducible cre line in the Wnt2 locus generated in our lab (Wnt2creERT2), we also show that Wnt2+ progenitors contribute to different mesenchymal lineages within the developing lung in a temporal restricted pattern and generate alveolar mesenchymal cells within the adult lung that can contribute to the generation of myofibroblasts in a model of lung fibrosis. Taken together these data suggest a critical role for Wnt signaling in two poorly understood processes in lung development and homeostasis: 1) domain branching in a temporal restricted fashion that when disrupted leads to congenital lung disease and 2) differentiation of specific mesenchymal lineages within the developing and postnatal lung through Wnt2 signaling. Using the new tools and techniques we have generated in the last round of funding we will 1) define the molecular pathways underlying the regulation of domain branching by Wnt/Fzd2 function and determine whether defects in Wnt signaling occur in CCAM lesions in humans, and 2) determine the contribution of Wnt2+ (Wnt expressing) and axin2+ (Wnt responsive) cells to lung mesenchymal development and the postnatal response to fibrotic injury models.
Wnt signaling is an important regulator of multiple aspects of lung development including respiratory endoderm specification, epithelial differentiation, and many aspects of the postnatal response to injury. However, there have been few studies to examine the direct connection between Wnt signaling and specific lung diseases. While Wnt signaling is activated in lung fibrosis and lung diseases involving smooth muscle hyperplasia including asthma and pulmonary hypertension, little is known about the causative role Wnt plays in lung disease. Our preliminary data also show a strong correlation between Wnt signaling and pediatric cystic lung disease such as CCAMs. Wnt signaling is a focus of therapeutic intervention as several agonists and antagonists have been developed opening the possibility of their use in pulmonary diseases. Given the dramatic affect that loss and gain of Wnt signaling have on lung progenitor development and adult regeneration from our published and preliminary studies, continued characterization of whether this important pathway is causative in pediatric and postnatal lung disease as well as the potential mechanisms of how Wnt affects lung regeneration will have a profound impact on development of future therapies for human lung disease.
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