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

Autophagy is required for lung development and morphogenesis

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 5

BECN1 is required for normal lung development and morphogenesis.

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BECN1 is required for normal lung development and morphogenesis. (A) Rep...
(A) Representative light photomicrographs of H&E-stained lung sections from littermate control and Becn1Epi-KO pups after birth. Inserts are representative photographs of littermate control and lung-specific Becn1Epi-KO pups immediately after birth. Scale bars: 70 μm. (B) Representative light photomicrographs of H&E-stained lung sections from littermate control and lung-specific Becn1Epi-KO littermates at different stages of lung development (E13.5, E16.5, and E18.5). Scale bars: 50 μm. (C) Graph shows the radial saccular count for E18.5 lungs from control (WT) mice and Becn1Epi-KO littermates. Data represent the mean ± SEM (n = 5 separate mouse lungs). *P < 0.05 versus control, by Student’s t test. (D) Representative explant cultures of E11.5 control (WT) and Becn1Epi-KO lung tissue that was cultured for 72 hours to evaluate branching morphogenesis. Graph indicates the number of terminal air sacs expressed as the mean ± SEM (n = 5 separate experiments). *P < 0.05 versus control, by Student’s t test.