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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.<\/jats:p>","DOI":"10.1242\/bio.019208","type":"journal-article","created":{"date-parts":[[2016,9,17]],"date-time":"2016-09-17T00:48:26Z","timestamp":1474073306000},"page":"1595-1606","source":"Crossref","is-referenced-by-count":33,"title":["Lethal lung hypoplasia and vascular defects in mice with conditional<i>Foxf1<\/i>overexpression"],"prefix":"10.1242","volume":"5","author":[{"given":"Avinash V.","family":"Dharmadhikari","sequence":"first","affiliation":[{"name":"Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Program in Translational Biology & Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny J.","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krzysztof","family":"Gogolewski","sequence":"additional","affiliation":[{"name":"Institute of Informatics , University of Warsaw, Warsaw 02-097, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandi L.","family":"Carofino","sequence":"additional","affiliation":[{"name":"Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Program in Translational Biology & Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir","family":"Ustiyan","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Misty","family":"Hill","sequence":"additional","affiliation":[{"name":"Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadeusz","family":"Majewski","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Przemyslaw","family":"Szafranski","sequence":"additional","affiliation":[{"name":"Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica J.","family":"Justice","sequence":"additional","affiliation":[{"name":"Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Program in Translational Biology & Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Genetics & Genome Biology Program, SickKids, Toronto, Ontario M5G 0A4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell S.","family":"Ray","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary E.","family":"Dickinson","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir V.","family":"Kalinichenko","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Gambin","sequence":"additional","affiliation":[{"name":"Institute of Informatics , University of Warsaw, Warsaw 02-097, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6456-7490","authenticated-orcid":false,"given":"Pawe\u0142","family":"Stankiewicz","sequence":"additional","affiliation":[{"name":"Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Program in Translational Biology & Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042423345107900_BIO019208C1","doi-asserted-by":"publisher","first-page":"993","DOI":"10.3892\/ijo.2011.921","article-title":"Differential expression of invasion promoting genes in childhood rhabdomyosarcoma","volume":"38","author":"Armeanu-Ebinger","year":"2011","journal-title":"Int. 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