Characterization of a new subfamily of winged-helix/forkhead (Fox) genes that are expressed in the lung and act as transcriptional repressors

Epithelial gene expression in the lungis thought to be regulated by the coo rdinate activity of several different families of transcription factors inc luding the Fox family of winged-helix/forkhead DNA-binding proteins. In thi s report, we have identified and characterized two members of this Fox gene family Foxp1 and Foxp2, and show that they comprise a new subfamily of Fox genes expressed in the lung, Foxp1 and Foxp2 are expressed at high levels in the lung as early as E12.5 of mouse development with Foxp2 expression re stricted to the airway epithelium. In addition, Foxp1 and Foxp2 are express ed at lower levels in neural, intestinal, and cardiovascular tissues during development. Upon differentiation of the airway epithelium along the proxi mal-distal axis, Foxp2 expression becomes restricted to the distal alveolar epithelium whereas Foxp1 expression is observed in the distal epithelium a nd mesenchyme. Foxp1 and Foxp2 can regulate epithelial lung gene transcript ion as was demonstrated by their ability to dramatically repress the mouse CC10 promoter and, to a lesser extent, the human surfactant protein C promo ter. In addition, GAL4 fusion proteins encoding subdomains of Foxp1 and Fox p2 demonstrate that an independent and homologous transcriptional repressio n domain lies within the N-terminal end of the proteins. Together, these st udies suggest that Foxp1 and Foxp2 are important regulators of lung epithel ial gene transcription.