Lethal lung hypoplasia and vascular defects in mice with conditional Foxf1 overexpression

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...

Full description

Saved in:

Bibliographic Details
Published in:	Biology open Vol. 5; no. 11; pp. 1595 - 1606
Main Authors:	Dharmadhikari, Avinash V, Sun, Jenny J, Gogolewski, Krzysztof, Carofino, Brandi L, Ustiyan, Vladimir, Hill, Misty, Majewski, Tadeusz, Szafranski, Przemyslaw, Justice, Monica J, Ray, Russell S, Dickinson, Mary E, Kalinichenko, Vladimir V, Gambin, Anna, Stankiewicz, Paweł
Format:	Journal Article
Language:	English
Published:	England The Company of Biologists Ltd 15-11-2016 The Company of Biologists
Subjects:	Abnormalities ACDMPV Alveoli Computed tomography Developmental disabilities Dosage Dysplasia Edema Embryos Gene therapy Hemorrhage Histopathology Hypoplasia Immunohistochemistry Liquid oxygen Lung development Lungs Misalignment Mutation Neonates Plethysmography Pulmonary vasculature Transcriptomes Pulmonary vasculature ACDMPV Lung development
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work
ISSN:	2046-6390 2046-6390
DOI:	10.1242/bio.019208