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14-3-3ζ loss leads to neonatal lethality by microRNA-126 downregulation-mediated developmental defects in lung vasculature
BACKGROUND: The 14-3-3 family of proteins have been reported to play an important role in development in various mouse models, but the context specific developmental functions of 14-3-3ζ remain to be determined. In this study, we identified a context specific developmental function of 14-3-3ζ. RESUL...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5667492/ https://www.ncbi.nlm.nih.gov/pubmed/29118970 http://dx.doi.org/10.1186/s13578-017-0186-y |
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author | Yang, Jun Joshi, Sonali Wang, Qingfei Li, Ping Wang, Hai Xiong, Yan Xiao, Yi Wang, Jinyang Parker-Thornburg, Jan Behringer, Richard R. Yu, Dihua |
author_facet | Yang, Jun Joshi, Sonali Wang, Qingfei Li, Ping Wang, Hai Xiong, Yan Xiao, Yi Wang, Jinyang Parker-Thornburg, Jan Behringer, Richard R. Yu, Dihua |
author_sort | Yang, Jun |
collection | PubMed |
description | BACKGROUND: The 14-3-3 family of proteins have been reported to play an important role in development in various mouse models, but the context specific developmental functions of 14-3-3ζ remain to be determined. In this study, we identified a context specific developmental function of 14-3-3ζ. RESULTS: Targeted deletion of 14-3-3ζ in the C57Bl/6J murine genetic background led to neonatal lethality due to respiratory distress and could be rescued by out-breeding to the CD-1 or backcrossing to the FVB/NJ congenic background. Histological analysis of lung sections from 18.5 days post coitum embryos (dpc) showed that 14-3-3ζ−/− lung development is arrested at the pseudoglandular stage and exhibits vascular defects. The expression of miR-126, an endothelial-specific miRNA known to regulate lung vascular integrity was down-regulated in the lungs of the 14-3-3ζ−/− embryos in the C57Bl/6J background as compared to their wild-type counterparts. Loss of 14-3-3ζ in endothelial cells inhibited the angiogenic capability of the endothelial cells as determined by both trans-well migration assays and tube formation assays and these defects could be rescued by re-expressing miR-126. Mechanistically, loss of 14-3-3ζ led to reduced Erk1/2 phosphorylation resulting in attenuated binding of the transcription factor Ets2 on the miR-126 promoter which ultimately reduced expression of miR-126. CONCLUSION: Our data demonstrates that miR-126 is an important angiogenesis regulator that functions downstream of 14-3-3ζ and downregulation of miR-126 plays a critical role in 14-3-3ζ-loss induced defects in lung vasculature in the C57Bl/6J genetic background. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13578-017-0186-y) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5667492 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-56674922017-11-08 14-3-3ζ loss leads to neonatal lethality by microRNA-126 downregulation-mediated developmental defects in lung vasculature Yang, Jun Joshi, Sonali Wang, Qingfei Li, Ping Wang, Hai Xiong, Yan Xiao, Yi Wang, Jinyang Parker-Thornburg, Jan Behringer, Richard R. Yu, Dihua Cell Biosci Research BACKGROUND: The 14-3-3 family of proteins have been reported to play an important role in development in various mouse models, but the context specific developmental functions of 14-3-3ζ remain to be determined. In this study, we identified a context specific developmental function of 14-3-3ζ. RESULTS: Targeted deletion of 14-3-3ζ in the C57Bl/6J murine genetic background led to neonatal lethality due to respiratory distress and could be rescued by out-breeding to the CD-1 or backcrossing to the FVB/NJ congenic background. Histological analysis of lung sections from 18.5 days post coitum embryos (dpc) showed that 14-3-3ζ−/− lung development is arrested at the pseudoglandular stage and exhibits vascular defects. The expression of miR-126, an endothelial-specific miRNA known to regulate lung vascular integrity was down-regulated in the lungs of the 14-3-3ζ−/− embryos in the C57Bl/6J background as compared to their wild-type counterparts. Loss of 14-3-3ζ in endothelial cells inhibited the angiogenic capability of the endothelial cells as determined by both trans-well migration assays and tube formation assays and these defects could be rescued by re-expressing miR-126. Mechanistically, loss of 14-3-3ζ led to reduced Erk1/2 phosphorylation resulting in attenuated binding of the transcription factor Ets2 on the miR-126 promoter which ultimately reduced expression of miR-126. CONCLUSION: Our data demonstrates that miR-126 is an important angiogenesis regulator that functions downstream of 14-3-3ζ and downregulation of miR-126 plays a critical role in 14-3-3ζ-loss induced defects in lung vasculature in the C57Bl/6J genetic background. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13578-017-0186-y) contains supplementary material, which is available to authorized users. BioMed Central 2017-11-02 /pmc/articles/PMC5667492/ /pubmed/29118970 http://dx.doi.org/10.1186/s13578-017-0186-y Text en © The Author(s) 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Yang, Jun Joshi, Sonali Wang, Qingfei Li, Ping Wang, Hai Xiong, Yan Xiao, Yi Wang, Jinyang Parker-Thornburg, Jan Behringer, Richard R. Yu, Dihua 14-3-3ζ loss leads to neonatal lethality by microRNA-126 downregulation-mediated developmental defects in lung vasculature |
title | 14-3-3ζ loss leads to neonatal lethality by microRNA-126 downregulation-mediated developmental defects in lung vasculature |
title_full | 14-3-3ζ loss leads to neonatal lethality by microRNA-126 downregulation-mediated developmental defects in lung vasculature |
title_fullStr | 14-3-3ζ loss leads to neonatal lethality by microRNA-126 downregulation-mediated developmental defects in lung vasculature |
title_full_unstemmed | 14-3-3ζ loss leads to neonatal lethality by microRNA-126 downregulation-mediated developmental defects in lung vasculature |
title_short | 14-3-3ζ loss leads to neonatal lethality by microRNA-126 downregulation-mediated developmental defects in lung vasculature |
title_sort | 14-3-3ζ loss leads to neonatal lethality by microrna-126 downregulation-mediated developmental defects in lung vasculature |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5667492/ https://www.ncbi.nlm.nih.gov/pubmed/29118970 http://dx.doi.org/10.1186/s13578-017-0186-y |
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