TRANSCRIPTION FACTORS | Fox

The Forkhead box (Fox) proteins are an extensive family of transcription factors, which share homology in the winged helix/forkhead DNA-binding domain. Mutations of the Fox genes elicit pronounced defects of cellular proliferation, differentiation, and metabolic homeostasis, leading to developmental abnormalities and human disease. In this review we will focus on Fox family members that contribute to lung development and disease. Deletion of the Foxa2 (HNF-3β) gene from respiratory epithelial cells is associated with airspace enlargement, goblet cell hyperplasia, and neutrophilic infiltration. Likewise, increased expression of Foxa2 in the distal respiratory epithelium caused a striking inhibition in branching morphogenesis and vasculogenesis of the lung. Foxj1 (HFH-4) deficient (−/−) mice display perinatal lethality due to defective differentiation of ciliated epithelial cells lining the pulmonary bronchioles and cerebral ventricles, leading to defects in lung function and hydrocephalus. Haploinsufficiency of the Foxf1 (HFH-8) gene causes fusion of the lung lobes and abnormal development of peripheral lung capillaries leading to perinatal pulmonary hemorrhage in 50% of the newborn Foxf1+/− mice that displayed an 80% reduction in lung expression levels of Foxf1. Earlier expression of the Foxm1b (HFH-11b) protein in transgenic mice following lung injury accelerates the onset of proliferation of different lung cell types. This partial list of genetic studies examining Fox proteins underscores the importance of this family in regulating genes involved in lung morphogenesis, respiratory diseases, and lung repair.