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Autophagy is required for lung development and morphogenesis
Behzad Yeganeh, … , Cameron Ackerley, Martin Post
Behzad Yeganeh, … , Cameron Ackerley, Martin Post
Published July 1, 2019; First published June 4, 2019
Citation Information: J Clin Invest. 2019;129(7):2904-2919. https://doi.org/10.1172/JCI127307.
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Categories: Research Article Development Pulmonology

Autophagy is required for lung development and morphogenesis

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Abstract

Bronchopulmonary dysplasia (BPD) remains a major respiratory illness in extremely premature infants. The biological mechanisms leading to BPD are not fully understood, although an arrest in lung development has been implicated. The current study aimed to investigate the occurrence of autophagy in the developing mouse lung and its regulatory role in airway branching and terminal sacculi formation. We found 2 windows of epithelial autophagy activation in the developing mouse lung, both resulting from AMPK activation. Inhibition of AMPK-mediated autophagy led to reduced lung branching in vitro. Conditional deletion of beclin 1 (Becn1) in mouse lung epithelial cells (Becn1Epi-KO), either at early (E10.5) or late (E16.5) gestation, resulted in lethal respiratory distress at birth or shortly after. E10.5 Becn1Epi-KO lungs displayed reduced airway branching and sacculi formation accompanied by impaired vascularization, excessive epithelial cell death, reduced mesenchymal thinning of the interstitial walls, and delayed epithelial maturation. E16.5 Becn1Epi-KO lungs had reduced terminal air sac formation and vascularization and delayed distal epithelial differentiation, a pathology similar to that seen in infants with BPD. Taken together, our findings demonstrate that intrinsic autophagy is an important regulator of lung development and morphogenesis and may contribute to the BPD phenotype when impaired.

Authors

Behzad Yeganeh, Joyce Lee, Leonardo Ermini, Irene Lok, Cameron Ackerley, Martin Post

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Figure 6

Conditional deletion of epithelial Becn1 affects mesenchymal thinning of the developing lung.

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Conditional deletion of epithelial Becn1 affects mesenchymal thinning of...
(A) Co-IF staining of CDH1 (green) and vimentin (red) in Becn1Epi-KO and littermate control lungs at E18.5. Nuclei were stained with DAPI (blue). Scale bars: 50 μm; original magnification, ×40 (insets). (B) Representative Western blot for CDH1, vimentin, and fibronectin. Graphs show the densitometric analysis of CDH1 and vimentin expression in whole-lung lysates harvested from Becn1Epi-KO and littermate controls at E18.5. ACTB was used as a protein loading control. Data represent the mean ± SEM (n = 4 separate lungs). *P < 0.05 versus control, by Student’s t test.
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