title: Foxp transcription factors suppress a non-pulmonary gene expression program to permit proper lung development.
abstract: The inhibitory mechanisms that prevent gene expression programs from one tissue to be expressed in another are poorly understood. Foxp1/2/4 are forkhead transcription factors that repress gene expression and are individually important for endoderm development. We show that combined loss of all three Foxp1/2/4 family members in the developing anterior foregut endoderm leads to a loss of lung endoderm lineage commitment and subsequent development. Foxp1/2/4 deficient lungs express high levels of transcriptional regulators not normally expressed in the developing lung, including Pax2, Pax8, Pax9 and the Hoxa9-13 cluster. Ectopic expression of these transcriptional regulators is accompanied by decreased expression of lung restricted transcription factors including Nkx2-1, Sox2, and Sox9. Foxp1 binds to conserved forkhead DNA binding sites within the Hoxa9-13 cluster, indicating a direct repression mechanism. Thus, Foxp1/2/4 are essential for promoting lung endoderm development by repressing expression of non-pulmonary transcription factors.
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States; Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, PA 19104, United States; Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, United States.
authors.forename: Shanru
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States; Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, PA 19104, United States; Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Morley
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States; Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, PA 19104, United States.
authors.forename: MinMin
authors.initials: M
authors.lastname: Lu
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States; Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, PA 19104, United States.
authors.forename: Su
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States; Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, PA 19104, United States; Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, United States.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Stewart
authors.affiliation: Champalimaud Neuroscience Programme, Champalimuad Centre for the Unknown, Lisbon, Portugal.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: French
authors.affiliation: Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, United States.
authors.forename: Haley O
authors.initials: HO
authors.lastname: Tucker
authors.affiliation: Language and Genetics Department, Max Plank Institute for Psycholinguistics, Nijmegen, The Netherlands.
authors.forename: Simon E
authors.initials: SE
authors.lastname: Fisher
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States; Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, PA 19104, United States; Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, United States; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, United States; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States. Electronic address: emorrise@mail.med.upenn.edu.
authors.forename: Edward E
authors.initials: EE
authors.lastname: Morrisey
mesh_terms: D000818:Animals; D001665:Binding Sites; D017124:Conserved Sequence; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004707:Endoderm / Q000166:cytology / Q000196:embryology; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005801:Genes, Homeobox; D008168:Lung / Q000196:embryology*; D051379:Mice; D009928:Organ Specificity; D038081:Organogenesis; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D051858:Forkhead Transcription Factors; C432917:Foxp1 protein, mouse; C432918:Foxp2 protein, mouse; C472854:Foxp4 protein, mouse; D012097:Repressor Proteins; D014157:Transcription Factors; D004247:DNA