title: Deletion of STK40 protein in mice causes respiratory failure and death at birth.
abstract: STK40 is a putative serine/threonine kinase and was shown to induce extraembryonic endoderm differentiation from mouse embryonic stem cells. However, little is known about its physiological function in vivo. Here, we generate Stk40 knock-out mice and demonstrate that loss of the Stk40 gene causes neonatal lethality at birth. Further examination reveals that the respiratory distress and atelectasis occur in the homozygous mutants. The maturation of lung and alveolar epithelium is delayed in the mutant, as indicated by narrowed air spaces, thickened interstitial septa, and increased glycogen content in the lungs of Stk40(-/-) mice. The reduction in levels of T1-α, SP-B, and SP-C indicates delayed maturation of both type I and type II respiratory epithelial cells in Stk40(-/-) lungs. Moreover, Stk40 is found to be most highly expressed in lungs of both fetal and adult mice among all organs tested. Mechanistically, a genome-wide RNA microarray analysis reveals significantly altered expression of multiple genes known to participate in lung development. The expression of some genes involved in lipid metabolism, immune response, and glycogen metabolism is also disrupted in the lung of Stk40(-/-) mice. Protein affinity purification identifies RCN2, an activator of ERK/MAPK signaling, as an STK40-associated protein. Consistently, Stk40 deficiency attenuates the ERK/MAPK activation, and inhibition of ERK/MAPK activities reduces surfactant protein gene expression in lung epithelial cells. Collectively, this study uncovers an important role of STK40 for lung maturation and neonatal survival. STK40 may associate with RCN2 to activate ERK/MAPK signaling and control the expression of multiple key regulators of lung development.
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai JiaoTong University School of Medicine, 225 South Chongqing Road, Shanghai 200025, China.
authors.forename: Hongyao
authors.initials: H
authors.lastname: Yu
authors.forename: Ke
authors.initials: K
authors.lastname: He
authors.forename: Lingjie
authors.initials: L
authors.lastname: Li
authors.forename: Lei
authors.initials: L
authors.lastname: Sun
authors.forename: Fan
authors.initials: F
authors.lastname: Tang
authors.forename: Ruizhen
authors.initials: R
authors.lastname: Li
authors.forename: Wen
authors.initials: W
authors.lastname: Ning
authors.forename: Ying
authors.initials: Y
authors.lastname: Jin
mesh_terms: D000818:Animals; D004848:Epithelium / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D055106:Genome-Wide Association Study; D005838:Genotype; D005982:Glutathione Transferase / Q000378:metabolism; D008168:Lung / Q000196:embryology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology; D011650:Pulmonary Alveoli / Q000378:metabolism; D011663:Pulmonary Surfactants / Q000378:metabolism; D012131:Respiratory Insufficiency / Q000235:genetics* / Q000401:mortality; D013997:Time Factors
chemical_list: D011663:Pulmonary Surfactants; D005982:Glutathione Transferase; D017346:Protein Serine-Threonine Kinases; C547661:Stk40 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases