title: Disruption of sorting nexin 5 causes respiratory failure associated with undifferentiated alveolar epithelial type I cells in mice.
abstract: Sorting nexin 5 (Snx5) has been posited to regulate the degradation of epidermal growth factor receptor and the retrograde trafficking of cation-independent mannose 6-phosphate receptor/insulin-like growth factor II receptor. Snx5 has also been suggested to interact with Mind bomb-1, an E3 ubiquitin ligase that regulates the activation of Notch signaling. However, the in vivo functions of Snx5 are largely unknown. Here, we report that disruption of the Snx5 gene in mice (Snx5(-/-) mice) resulted in partial perinatal lethality; 40% of Snx5(-/-) mice died shortly after birth due to cyanosis, reduced air space in the lungs, and respiratory failure. Histological analysis revealed that Snx5(-/-) mice exhibited thickened alveolar walls associated with undifferentiated alveolar epithelial type I cells. In contrast, alveolar epithelial type II cells were intact, exhibiting normal surfactant synthesis and secretion. Although the expression levels of surfactant proteins and saturated phosphatidylcholine in the lungs of Snx5(-/-) mice were comparable to those of Snx5(+/+) mice, the expression levels of T1α, Aqp5, and Rage, markers for distal alveolar epithelial type I cells, were significantly decreased in Snx5 (-/-) mice. These results demonstrate that Snx5 is necessary for the differentiation of alveolar epithelial type I cells, which may underlie the adaptation to air breathing at birth.
authors.affiliation: School of Biological Science, College of Natural Sciences, Seoul National University, Seoul, South Korea.
authors.forename: Sun-Kyoung
authors.initials: SK
authors.lastname: Im
authors.forename: HyoBin
authors.initials: H
authors.lastname: Jeong
authors.forename: Hyun-Woo
authors.initials: HW
authors.lastname: Jeong
authors.forename: Kyong-Tai
authors.initials: KT
authors.lastname: Kim
authors.forename: Daehee
authors.initials: D
authors.lastname: Hwang
authors.forename: Machiko
authors.initials: M
authors.lastname: Ikegami
authors.forename: Young-Yun
authors.initials: YY
authors.lastname: Kong
mesh_terms: D056809:Alveolar Epithelial Cells / Q000145:classification / Q000473:pathology / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011247:Pregnancy; D011650:Pulmonary Alveoli / Q000002:abnormalities; D037661:Pulmonary Surfactant-Associated Proteins / Q000235:genetics / Q000378:metabolism; D012131:Respiratory Insufficiency / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D058305:Sorting Nexins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
chemical_list: D037661:Pulmonary Surfactant-Associated Proteins; C533712:Snx5 protein, mouse; D058305:Sorting Nexins