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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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Company of Biologists Ltd
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155529/ https://www.ncbi.nlm.nih.gov/pubmed/27638768 http://dx.doi.org/10.1242/bio.019208 |
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author | 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 |
author_facet | 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 |
author_sort | Dharmadhikari, Avinash V. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5155529 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | The Company of Biologists Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-51555292016-12-16 Lethal lung hypoplasia and vascular defects in mice with conditional Foxf1 overexpression 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 Biol Open Research Article 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. The Company of Biologists Ltd 2016-09-16 /pmc/articles/PMC5155529/ /pubmed/27638768 http://dx.doi.org/10.1242/bio.019208 Text en © 2016. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
spellingShingle | Research Article 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 Lethal lung hypoplasia and vascular defects in mice with conditional Foxf1 overexpression |
title | Lethal lung hypoplasia and vascular defects in mice with conditional Foxf1 overexpression |
title_full | Lethal lung hypoplasia and vascular defects in mice with conditional Foxf1 overexpression |
title_fullStr | Lethal lung hypoplasia and vascular defects in mice with conditional Foxf1 overexpression |
title_full_unstemmed | Lethal lung hypoplasia and vascular defects in mice with conditional Foxf1 overexpression |
title_short | Lethal lung hypoplasia and vascular defects in mice with conditional Foxf1 overexpression |
title_sort | lethal lung hypoplasia and vascular defects in mice with conditional foxf1 overexpression |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155529/ https://www.ncbi.nlm.nih.gov/pubmed/27638768 http://dx.doi.org/10.1242/bio.019208 |
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