Foxm1 Mediates Cross Talk between Kras/Mitogen-Activated Protein Kinase and Canonical Wnt Pathways during Development of Respiratory Epithelium

While Kras/mitogen-activated protein kinase (MAPK) and canonical Wnt/-catenin are critical for lung morphogenesis, mecha-nisms integrating these important signaling pathways during lung development are unknown. Herein, we demonstrate that the Foxm1 transcription factor is a key downstream target of activated KrasG12D. Deletion of Foxm1 from respiratory epithelial cells during lung formation prevented structural abnormalities caused by activated KrasG12D. Kras/Foxm1 signaling inhibited the activity of canonical Wnt signaling in the developing lung in vivo. Foxm1 decreased T-cell factor (TCF) transcriptional activity induced by activated -catenin in vitro. Depletion of Foxm1 by short interfering RNA (siRNA) increased nuclear localization of -catenin, increased expression of -catenin target genes, and decreased mRNA and protein levels of the -catenin inhibitor Axin2. Axin2 mRNAwas reduced in distal lung epithelium of Foxm1-deficient mice. Foxm1 directly bound to and increased transcriptional activity of the Axin2 promoter region. Foxm1 is required for Kras signaling in distal lung epithelium and pro-vides a mechanism integrating Kras and canonical Wnt/-catenin signaling during lung development. Lung formation is controlled by receptor-mediated signalingevents between mesenchyme and foregut endoderm-derived epithelial cells that regulate the gene expression required for branching lung morphogenesis (34, 44). Stereotypic branching results in the formation of conducting airways and peripheral sac-cules which form the alveoli that mediate gas exchange after birt