title: Foxf genes integrate tbx5 and hedgehog pathways in the second heart field for cardiac septation.
abstract: The Second Heart Field (SHF) has been implicated in several forms of congenital heart disease (CHD), including atrioventricular septal defects (AVSDs). Identifying the SHF gene regulatory networks required for atrioventricular septation is therefore an essential goal for understanding the molecular basis of AVSDs. We defined a SHF Hedgehog-dependent gene regulatory network using whole genome transcriptional profiling and GLI-chromatin interaction studies. The Forkhead box transcription factors Foxf1a and Foxf2 were identified as SHF Hedgehog targets. Compound haploinsufficiency for Foxf1a and Foxf2 caused atrioventricular septal defects, demonstrating the biological relevance of this regulatory network. We identified a Foxf1a cis-regulatory element that bound the Hedgehog transcriptional regulators GLI1 and GLI3 and the T-box transcription factor TBX5 in vivo. GLI1 and TBX5 synergistically activated transcription from this cis-regulatory element in vitro. This enhancer drove reproducible expression in vivo in the posterior SHF, the only region where Gli1 and Tbx5 expression overlaps. Our findings implicate Foxf genes in atrioventricular septation, describe the molecular underpinnings of the genetic interaction between Hedgehog signaling and Tbx5, and establish a molecular model for the selection of the SHF gene regulatory network for cardiac septation.
authors.affiliation: Departments of Pediatrics, Pathology, and Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hoffmann
authors.affiliation: Departments of Pediatrics, Pathology, and Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Xinan Holly
authors.initials: XH
authors.lastname: Yang
authors.affiliation: Departments of Pediatrics, Pathology, and Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Ozanna
authors.initials: O
authors.lastname: Burnicka-Turek
authors.affiliation: Departments of Pediatrics, Pathology, and Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Bosman
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Ren
authors.affiliation: Departments of Pediatrics, Pathology, and Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Steimle
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, University of Texas, Austin, Texas, United States of America.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Vokes
authors.affiliation: Department of Regenerative Medicine and Stem Cell Biology, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: McMahon
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Kalinichenko
authors.affiliation: Departments of Pediatrics, Pathology, and Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Ivan P
authors.initials: IP
authors.lastname: Moskowitz
mesh_terms: D000818:Animals; D002843:Chromatin / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D006321:Heart / Q000503:physiopathology*; D006343:Heart Septal Defects / Q000235:genetics* / Q000473:pathology; D053823:Hedgehog Proteins / Q000235:genetics; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D000071676:Zinc Finger Protein GLI1; D000074290:Zinc Finger Protein Gli3
chemical_list: D002843:Chromatin; D051858:Forkhead Transcription Factors; C486293:Foxf1 protein, mouse; C486412:Foxf2 protein, mouse; C400551:GLI1 protein, human; C065683:GLI3 protein, human; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D000074290:Zinc Finger Protein Gli3