Wnt2/2b and β-Catenin Signaling Are Necessary and Sufficient to Specify Lung Progenitors in the Foregut

Abstract

The primitive foregut is patterned in a manner that spatially promotes proper organ specification along the anterior-posterior foregut axis. However, the molecular pathways that specify foregut endoderm progenitors are poorly understood. We show that Wnt2/2b signaling is required to specify lung endoderm progenitors within the anterior foregut. Embryos lacking Wnt2/2b expression exhibit complete lung agenesis and do not express Nkx2.1, the earliest marker of the lung endoderm. In contrast, other foregut endoderm derived organs including the thyroid, liver, and pancreas are correctly specified in Wnt2/2b null animals. We show that this phenotype is recapitulated by an endoderm restricted deletion of β-catenin, demonstrating that Wnt2/2b signaling through the canonical Wnt pathway is required to specify lung endoderm progenitors within the foregut. Moreover, activation of canonical Wnt/β-catenin signaling results in reprogramming of esophagus and stomach endoderm to a lung endoderm progenitor fate. Together, these data reveal that canonical Wnt2/2b signaling is uniquely required for specification of lung endoderm progenitors in the developing foregut.

The building blocks of mammalian lung development

“…Wnt2 is expressed in the mesenchyme surrounding the epithelial buds and also promotes lung progenitor proliferation. Similar to Wnt7b null animals, Wnt2 null mice have smaller lungs with both epithelial and mesenchymal proliferation defects, but normal overall patterning (Goss et al, 2009). Wnt5a is highly expressed in the distal lung epithelium and surrounding mesenchyme.…”

“…In addition, the molecular regulation of the adult lung progenitors may be different to that of their embryonic counterparts. Wnt signaling is required for embryonic progenitor proliferation Goss et al, 2009). However, specific deletion of b-catenin, which is necessary for canonical Wnt signaling, in a known adult lung progenitor population did not have any effect on airway epithelial growth, maintenance or repair (Zemke et al, 2009).…”

“…Wnt signaling has also been implicated in proximal-distal epithelial patterning and differentiation during lung development and the roles of other Wnt ligands remain obscure (Shu et al, 2005;Zhang et al, 2008). Interestingly, Wnt signaling is also absolutely required for the initial specification of the respiratory epithelial lineage from the foregut endoderm (Goss et al, 2009;Harris-Johnson et al, 2009;Chen et al, 2010).…”

Take the Wnt out of the inflammatory sails: modulatory effects of Wnt in airway diseases

“…A potential option for the future could be the reactivation of signaling pathways that are active during lung development to induce epithelial repair in the damaged areas similar to the Wnt/β-catenin pathway. 70,105,106 In human lung samples of patients with COPD, a reduction of nuclear β-catenin is detectable. 64 In addition, decreased Wnt/β-catenin activation has been described in different murine models of emphysema and treatment with LiCl attenuated airspace enlargement and prevents the development of emphysema.…”

The evolving concept of cancer stem-like cells in thyroid cancer and other solid tumors

“…Experimental evidence has shown that Wnt2/2b and β-catenin signaling are necessary and sufficient to specify lung progenitors in the foregut. 51 The role of the Wnt pathway in thyroid cancer and CSCs has been studied using primary thyroid cancer cells. 7 CSCs isolated from ATCs were most aggressive and tumorigenic compared with CSCs isolated from well differentiated papillary and follicular cancers.…”