E3 ubiquitin ligase FBXW7 balances airway cell fates

The airway epithelium is composed of multiple cell types each with designated roles. A stereotyped ratio of these cells is essential for proper airway function. Imbalance of airway cell types underlies many lung diseases, including chronic obstructive pulmonary disease (COPD) and asthma. While a number of signals and transcription factors have been implicated in airway cell specification, how cell numbers are coordinated, especially at the protein level is poorly understood. Here we show that in the mouse trachea which contain epithelial cell types similar to human airway, epithelium-specific inactivation of Fbxw7, which encodes an E3 ubiquitin ligase, led to reduced club and ciliated cells, increased goblet cells, and ectopic P63-negative, Keratin5-positive transitory basal cells in the luminal layer. The protein levels of FBXW7 targets including NOTCH1, KLF5 and TGIF were increased. Inactivation of either Notch1, Klf5 but not Tgif genes in the mutant background led to attenuation of selected aspects of the phenotypes, suggesting that FBXW7 acts through different targets to control different cell fates. These findings demonstrate that protein-level regulation by the ubiquitin proteasome system is critical for balancing airway cell fates.