The Fgf9-Nolz1-Wnt2 axis regulates morphogenesis of the lung.

Morphological development of the lung requires complex signal crosstalk between the mesenchymal and epithelial progenitors. Elucidating the genetic cascades underlying signal crosstalk is essential to understanding lung morphogenesis. Here, we identified Nolz1 as a mesenchymal lineage-specific transcriptional regulator that plays a key role in lung morphogenesis. Nolz1 null mutation resulted in a severe hypoplasia phenotype, including a decreased proliferation of mesenchymal cells, aberrant differentiation of epithelial cells and defective growth of epithelial branches. Nolz1 deletion also downregulated Wnt2, Lef1, Fgf10, Gli3 and Bmp4 mRNAs. Mechanistically, Nolz1 regulates lung morphogenesis primarily through Wnt2 signaling. Loss-of-function and overexpression studies demonstrated that Nolz1 transcriptionally activated Wnt2 and downstream β-catenin signaling to control mesenchymal cell proliferation and epithelial branching. Exogenous Wnt2 could rescue defective proliferation and epithelial branching in Nolz1 knockout lungs. Finally, we identified Fgf9 as an upstream regulator of Nolz1. Collectively, Fgf9-Nolz1-Wnt2 signaling represents a novel axis in the control of lung morphogenesis. These findings are relevant to lung tumorigenesis, in which a pathological function of Nolz1 is implicated.