Fgf9-Nolz-1-Wnt2 Signaling Axis Regulates Morphogenesis of the Lung

Abstract

Morphological development of the lung requires complex signal crosstalk between the mesenchymal and epithelial progenitors. Elucidating the genetic cascades underlying the signal crosstalk is essential to understanding the morphogenesis of the lung. Here, we have identified Nolz-1/Znf503 as a mesenchymal lineage-specific transcriptional regulator that plays a key role in lung morphogenesis. The null mutation of Nolz-1 resulted in a severe hypoplasia phenotype, including decreased proliferation of mesenchymal cells, aberrant differentiation of epithelial cells, and defective growth of epithelial branches. The deletion of Nolz-1 also downregulated the expressions of Wnt2, Lef1, Fgf10, Gli3 and Bmp4. Mechanistically, we found that Nolz-1 regulated lung morphogenesis primarily through Wnt2 signaling. Loss of function and overexpression studies demonstrated that Nolz-1 transcriptionally activated Wnt2 and downstream {beta}-catenin signaling to control mesenchymal cell proliferation and epithelial branching. The Nolz-1-Wnt2 axis was also supported by evidence that exogenous Wnt2 could causally rescue defective proliferation and epithelial branching in Nolz-1 knockout lungs. Finally, we have identified Fgf9 as an upstream regulator of Nolz-1. Collectively, Fgf9-Nolz-1-Wnt2 signaling represents a novel signaling axis in the control of lung morphogenesis. These findings are also relevant to lung tumorigenesis in which a pathological function of Nolz-1 is involved.