Disruption of sorting nexin 5 causes respiratory failure associated with undifferentiated alveolar epithelial type I cells in mice

PLoS One. 2013;8(3):e58511. doi: 10.1371/journal.pone.0058511. Epub 2013 Mar 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alveolar Epithelial Cells / classification
  • Alveolar Epithelial Cells / pathology
  • Alveolar Epithelial Cells / physiology*
  • Animals
  • Animals, Newborn
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Female
  • Gene Expression Regulation, Developmental
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pregnancy
  • Pulmonary Alveoli / abnormalities
  • Pulmonary Surfactant-Associated Proteins / genetics
  • Pulmonary Surfactant-Associated Proteins / metabolism
  • Respiratory Insufficiency / etiology*
  • Respiratory Insufficiency / pathology
  • Respiratory Insufficiency / physiopathology
  • Sorting Nexins / deficiency*
  • Sorting Nexins / genetics
  • Sorting Nexins / physiology


  • Pulmonary Surfactant-Associated Proteins
  • Snx5 protein, mouse
  • Sorting Nexins

Grant support

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (RND no. 2012-0000121), National R&D Program for Cancer Control, Ministry of Health & Welfare, the Republic of Korea (RND no. 0920310), Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MEST; RND no. 2011-0019269), and Global Frontier Project grant (RND no. 2011-0028413) of the National Research Foundation funded by the Ministry of Education, Science and Technology of Korea. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.