title: Analysis of a lung defect in autophagy-deficient mouse strains.
abstract: Yeast Atg1 initiates autophagy in response to nutrient limitation. The Ulk gene family encompasses the mammalian orthologs of yeast ATG1. We created mice deficient for both Ulk1 and Ulk2 and found that the mice die within 24 h of birth. When found alive, pups exhibited signs of respiratory distress. Histological sections of lungs of the Ulk1/2 DKO pups showed reduced airspaces with thickened septae. A similar defect was seen in Atg5-deficient pups as both Ulk1/2 DKO and Atg5 KO lungs show numerous glycogen-laden alveolar type II cells by electron microscopy, PAS staining, and increased levels of glycogen in lung homogenates. No abnormalities were noted in expression of genes encoding surfactant proteins but the ability to incorporate exogenous choline into phosphatidylcholine, the major phospholipid component of surfactant, was increased in comparison to controls. Despite this, there was a trend for total phospholipid levels in lung tissue to be lower in Ulk1/2 DKO and Atg5 KO compared with controls. Autophagy was abundant in lung epithelial cells from wild-type mice, but lacking in Atg5 KO and Ulk1/2 DKO mice at P1. Analysis of the autophagy signaling pathway showed the existence of a negative feedback loop between the ULK1 and 2 and MTORC1 and 2, in lung tissue. In the absence of autophagy, alveolar epithelial cells are unable to mobilize internal glycogen stores independently of surfactant maturation. Together, the data suggested that autophagy plays a vital role in lung structural maturation in support of perinatal adaptation to air breathing.
authors.affiliation: Cancer Biology and Genetics Program; Memorial Sloan-Kettering Cancer Center; New York, NY USA.
authors.forename: Heesun
authors.initials: H
authors.lastname: Cheong
authors.affiliation: Department of Cancer Biology; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Junmin
authors.initials: J
authors.lastname: Wu
authors.affiliation: Division of Neonatology; Department of Pediatrics; Children's Hospital of Philadelphia and the University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Linda K
authors.initials: LK
authors.lastname: Gonzales
authors.affiliation: Division of Neonatology; Department of Pediatrics; Children's Hospital of Philadelphia and the University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Susan H
authors.initials: SH
authors.lastname: Guttentag
authors.affiliation: Cancer Biology and Genetics Program; Memorial Sloan-Kettering Cancer Center; New York, NY USA.
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
authors.affiliation: Immunology Program; Memorial Sloan-Kettering Cancer Center; New York, NY USA.
authors.forename: Tullia
authors.initials: T
authors.lastname: Lindsten
mesh_terms: D056809:Alveolar Epithelial Cells / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D000818:Animals; D000831:Animals, Newborn; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D000071189:Autophagy-Related Protein-1 Homolog; D006003:Glycogen / Q000378:metabolism; D007150:Immunohistochemistry; D008168:Lung / Q000196:embryology / Q000473:pathology* / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000378:metabolism; D013194:Staining and Labeling
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D010743:Phospholipids; D006003:Glycogen; C401061:Ulk2 protein, mouse; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C112444:Ulk1 protein, mouse
keywords: Atg5KO mice; Ulk1/2DKO mice; glycogen; lung development; perinatal mortality