title: Lethal lung hypoplasia and vascular defects in mice with conditional Foxf1 overexpression.
abstract: FOXF1 heterozygous point mutations and genomic deletions have been reported in newborns with the neonatally lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). However, no gain-of-function mutations in FOXF1 have been identified yet in any human disease conditions. To study the effects of FOXF1 overexpression in lung development, we generated a Foxf1 overexpression mouse model by knocking-in a Cre-inducible Foxf1 allele into the ROSA26 (R26) locus. The mice were phenotyped using micro-computed tomography (micro-CT), head-out plethysmography, ChIP-seq and transcriptome analyses, immunohistochemistry, and lung histopathology. Thirty-five percent of heterozygous R26-Lox-Stop-Lox (LSL)-Foxf1 embryonic day (E)15.5 embryos exhibit subcutaneous edema, hemorrhages and die perinatally when bred to Tie2-cre mice, which targets Foxf1 overexpression to endothelial and hematopoietic cells. Histopathological and micro-CT evaluations revealed that R26Foxf1; Tie2-cre embryos have immature lungs with a diminished vascular network. Neonates exhibited respiratory deficits verified by detailed plethysmography studies. ChIP-seq and transcriptome analyses in E18.5 lungs identified Sox11, Ghr, Ednrb, and Slit2 as potential downstream targets of FOXF1. Our study shows that overexpression of the highly dosage-sensitive Foxf1 impairs lung development and causes vascular abnormalities. This has important clinical implications when considering potential gene therapy approaches to treat disorders of FOXF1 abnormal dosage, such as ACDMPV.
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.|Program in Translational Biology & Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Avinash V
authors.initials: AV
authors.lastname: Dharmadhikari
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jenny J
authors.initials: JJ
authors.lastname: Sun
authors.affiliation: Institute of Informatics, University of Warsaw, Warsaw 02-097, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Gogolewski
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.|Program in Translational Biology & Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Brandi L
authors.initials: BL
authors.lastname: Carofino
authors.affiliation: Division of Pulmonary Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ustiyan
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Misty
authors.initials: M
authors.lastname: Hill
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Majewski
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Szafranski
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.|Program in Translational Biology & Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.|Genetics & Genome Biology Program, SickKids, Toronto, Ontario M5G 0A4, Canada.
authors.forename: Monica J
authors.initials: MJ
authors.lastname: Justice
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Russell S
authors.initials: RS
authors.lastname: Ray
authors.affiliation: Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Dickinson
authors.affiliation: Division of Pulmonary Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Kalinichenko
authors.affiliation: Institute of Informatics, University of Warsaw, Warsaw 02-097, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Gambin
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA pawels@bcm.edu.|Program in Translational Biology & Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Paweł
authors.identifier: http://orcid.org/0000-0002-6456-7490
authors.initials: P
authors.lastname: Stankiewicz
keywords: ACDMPV; Lung development; Pulmonary vasculature