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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-?, 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.

SUBMITTER: Yu H

PROVIDER: S-EPMC3581428 | biostudies-other | 2013 Feb

REPOSITORIES: biostudies-other

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Deletion of STK40 protein in mice causes respiratory failure and death at birth.

Yu Hongyao H He Ke K Li Lingjie L Sun Lei L Tang Fan F Li Ruizhen R Ning Wen W Jin Ying Y

The Journal of biological chemistry 20130104 8

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 m ...[more]

PMID: 23293024

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Project description:We reported previously that adult (HRAS-/-; NRAS-/-) double knockout (DKO) mice showed no obvious external phenotype although lower-than-expected numbers of weaned DKO animals were consistently tallied after crossing NRAS-KO and HRAS-KO mice kept on mixed genetic backgrounds. Using mouse strains kept on pure C57Bl/6 background, here we performed an extensive analysis of the offspring from crosses between HRAS-KO and NRAS-KO mice and uncovered the occurrence of very high rates of perinatal mortality of the resulting DKO littermates due to respiratory failure during the first postnatal 24-48 h. The lungs of newborn DKO mice showed normal organ structure and branching but displayed marked defects of maturation including much-reduced alveolar space with thick separating septa and significant alterations of differentiation of alveolar (AT1, AT2 pneumocytes) and bronchiolar (ciliated, Clara cells) cell lineages. We also observed the retention of significantly increased numbers of undifferentiated progenitor precursor cells in distal lung epithelia and the presence of substantial accumulations of periodic acid-Schiff-positive (PAS+) material and ceramide in the lung airways of newborn DKO mice. Interestingly, antenatal dexamethasone treatment partially mitigated the defective lung maturation phenotypes and extended the lifespan of the DKO animals up to 6 days, but was not sufficient to abrogate lethality in these mice. RNA microarray hybridization analyses of the lungs of dexamethasone-treated and untreated mice uncovered transcriptional changes pointing to functional and metabolic alterations that may be mechanistically relevant for the defective lung phenotypes observed in DKO mice. Our data suggest that delayed alveolar differentiation, altered sphingolipid metabolism and ceramide accumulation are primary contributors to the respiratory stress and neonatal lethality shown by DKO mice and uncover specific, critical roles of HRAS and NRAS for correct lung differentiation that are essential for neonatal survival and cannot be substituted by the remaining KRAS function in this organ.

Project description:Selenoproteins are a small family of proteins containing the trace element selenium in form of the rare amino acid selenocysteine (Sec), which is decoded by the UGA codon. In humans, a number of pathogenic variants in genes encoding distinct selenoproteins or selenoprotein biosynthesis factors have been identified. Pathogenic variants in selenocysteine synthase (SEPSECS), which catalyzes the last step in Sec-tRNA[Ser]Sec biosynthesis, were reported in children suffering from progressive cerebello-cerebral atrophy. To understand the pathomechanism associated with SEPSECS deficiency, we generated a novel mouse model recapitulating the respective human pathogenic p.Y334C variant in the murine Sepsecs gene (SepsecsY334C). Unlike in patients, pups homozygous for the p.Y334C variant died perinatally with signs of cardio-respiratory failure. Perinatal death is reminiscent of the Sedaghatian spondylometaphyseal dysplasia disorder in humans, which is caused by pathogenic variants in the gene encoding the selenoprotein and key ferroptosis regulator glutathione peroxidase 4 (GPX4). Protein expression levels of distinct selenoproteins in SepsecsY334C/Y334C mice were found to be generally reduced in brain and isolated cortical neurons, while transcriptomics analysis uncovered an upregulation of NRF2-regulated genes. Crossbreeding of SepsecsY334C/Y334C mice with mice harboring a targeted mutation of the catalytically active Sec to Cys in GPX4 rescued perinatal death of SepsecsY334C/Y334C mice, showing that the cardio-respiratory defects of SepsecsY334C/Y334C mice were caused by the lack of GPX4. Like in SepsecsY334C/Y334C mice, selenoprotein expression levels remained low and NRF2-regulated genes remained highly expressed in these compound mutant mice, indicating that selenium-independent GPX4, along with a sustained antioxidant response are sufficient to compensate for dysfunctional Sec-tRNA[Ser]Sec biosynthesis. Our findings imply that children with pathogenic variants in SEPSECS or GPX4 may even benefit from treatments that incompletely compensate for impaired GPX4 activity.

Project description:BackgroundAcute hypoxemic respiratory failure (AHRF) and acute respiratory distress syndrome (ARDS) are associated with high in-hospital mortality. However, in cohorts of ARDS patients from the 1990s, patients more commonly died from sepsis or multi-organ failure rather than refractory hypoxemia. Given increased attention to lung-protective ventilation and sepsis treatment in the past 25 years, we hypothesized that causes of death may be different among contemporary cohorts. These differences may provide clinicians with insight into targets for future therapeutic interventions.MethodsWe identified adult patients hospitalized at a single tertiary care center (2016-2017) with AHRF, defined as PaO2/FiO2 ≤ 300 while receiving invasive mechanical ventilation for > 12 h, who died during hospitalization. ARDS was adjudicated by multiple physicians using the Berlin definition. Separate abstractors blinded to ARDS status collected data on organ dysfunction and withdrawal of life support using a standardized tool. The primary cause of death was defined as the organ system that most directly contributed to death or withdrawal of life support.ResultsWe identified 385 decedents with AHRF, of whom 127 (33%) had ARDS. The most common primary causes of death were sepsis (26%), pulmonary dysfunction (22%), and neurologic dysfunction (19%). Multi-organ failure was present in 70% at time of death, most commonly due to sepsis (50% of all patients), and 70% were on significant respiratory support at the time of death. Only 2% of patients had insupportable oxygenation or ventilation. Eighty-five percent died following withdrawal of life support. Patients with ARDS more often had pulmonary dysfunction as the primary cause of death (28% vs 19%; p = 0.04) and were also more likely to die while requiring significant respiratory support (82% vs 64%; p < 0.01).ConclusionsIn this contemporary cohort of patients with AHRF, the most common primary causes of death were sepsis and pulmonary dysfunction, but few patients had insupportable oxygenation or ventilation. The vast majority of deaths occurred after withdrawal of life support. ARDS patients were more likely to have pulmonary dysfunction as the primary cause of death and die while requiring significant respiratory support compared to patients without ARDS.

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Deletion of STK40 protein in mice causes respiratory failure and death at birth.

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Deletion of STK40 protein in mice causes respiratory failure and death at birth.

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