Pneumologie 2018; 72(03): 232
DOI: 10.1055/s-0037-1615335
Lungenregeneration
Georg Thieme Verlag KG Stuttgart · New York

MiR-154 controls alveologenesis in lung development via TGF-β signaling

CM Chao
1   Universities of Gießen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Department of Internal Medicine II, Gießen, Germany
2   University Children's Hospital Gießen, Division of General Pediatrics and Neonatology, Justus-Liebig-University, Gießen, Germany, Member of the German Lung Center (DZL)
,
G Carraro
3   Lung and Regenerative Medicine Institutes, Cedars-Sinai Medical Center, LA, USA
,
Z Rako
1   Universities of Gießen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Department of Internal Medicine II, Gießen, Germany
,
J Kolck
1   Universities of Gießen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Department of Internal Medicine II, Gießen, Germany
,
V Zimmermann
1   Universities of Gießen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Department of Internal Medicine II, Gießen, Germany
,
J Wilhem
1   Universities of Gießen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Department of Internal Medicine II, Gießen, Germany
,
W Seeger
1   Universities of Gießen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Department of Internal Medicine II, Gießen, Germany
,
RJ Rottier
4   Department of Pediatric Surgery, Erasmus Medical Center – Sophia Children's Hospital, Rotterdam, Netherlands
,
RE Morty
5   Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research
,
S Bellusci
1   Universities of Gießen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Department of Internal Medicine II, Gießen, Germany
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Publikationsverlauf

Publikationsdatum:
07. März 2018 (online)

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Objective:

MiR-154 is abundant in neonatal lungs and has been associated with several lung diseases (e.g. IPF). Experimental evidence for a direct effect of miR-154 on lung development is still lacking.

Results:

First, the expression of miR-154 from E10.5-P2 was analyzed by RT-qPCR and FISH. MiR-154 expression increased dynamically from E10.5 and peaks at P2. Attenuation of miR-154 in WT embryonic lung (CD1) harvested at E11.5 and treated with morpholino vs. control reveals a significant decreased in lung branching after 48h of culture. Prenatal overexpression of miR-154 from E7.5-E18.5 in CCSPrtTA/rtTA;tet(O)miR-154/+ mice (lung epithelial specific overexpression) and analysis of the lung structure by using alveolar morphometry shows increased mean linear intercept (MLI) and alveolar airspace but decrease in septal thickness indicating alveolarization defects. RT-qPCR reveals a decrease in Fgf10 signaling as well as markers for alveolar myofibroblast but increase in epithelial marker EpCAM. In contrast, postnatal overexpression of miR-154 by using CCSPrtTA/rtTA;tet(O)miR-154/+ from P0-P16.5 leads to increased Fgf and Tgf-β signaling in the mutant group as well as increased MLI without changes in airspace and septal thickness. Interestingly, pull-down assay reveals caveolin 1 (Cav1), which is responsible for Tgf-β/Tgf-βR degradation, as a target of miR-154.

Conclusions:

MiR-154 plays a crucial role in alveologenesis – possibly involving Tgf-β signaling.