Foxp2 and Foxp1 cooperatively regulate lung and esophagus development

The airways of the lung develop through a reiterative process of branching morphogenesis that gives rise to the intricate and extensive surface area required for postnatal respiration. The forkhead transcription factors Foxp2 and Foxp1 are expressed in multiple foregut-derived tissues including the lung and intestine. In this report, we show that loss of Foxp2 in mouse leads to defective postnatal lung alveolarization, contributing to postnatal lethality. Using in vitro and in vivo assays, we show that T1alpha, a lung alveolar epithelial type 1 cell-restricted gene crucial for lung development and function, is a direct target of Foxp2 and Foxp1. Remarkably, loss of a single Foxp1 allele in addition to complete loss of Foxp2 results in increased severity of morphological defects in mutant lungs and leads to perinatal loss of all Foxp2^-/-;Foxp1^+/- mice. Expression of N-myc and Hop, crucial regulators of lung development, is compromised in Foxp2^-/-;Foxp1^+/- mutants. In addition to the defects in lung development, esophageal muscle development is disrupted in Foxp2^-/-;Foxp1^+/- embryos, a tissue where Foxp2 and Foxp1 are co-expressed. These data identify Foxp2 and Foxp1 as crucial regulators of lung and esophageal development, underscoring the necessity of these transcription factors in the development of anterior foregut-derived tissues and demonstrating functional cooperativity between members of the Foxp1/2/4 family in tissues where they are co-expressed.