Deletion of STK40 Protein in Mice Causes Respiratory Failure and Death at Birth
Deletion of STK40 Protein in Mice Causes Respiratory Failure and Death at Birth
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DOI：
10.1074/jbc.m112.409433
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发表时间：
2013-02-22
影响因子：
4.8
通讯作者：
Jin, Ying
中科院分区：
文献类型：
--
作者：
Yu, Hongyao;He, Ke;Jin, Ying
STK40是一种丝氨酸/苏氨酸激酶，可以诱导小鼠胚胎干细胞分化为胚胎外内胚层。然而，人们对其在体内的生理功能知之甚少。在这里，我们产生了Stk40基因敲除的小鼠，并证明了Stk40基因的缺失会导致新生儿在出生时死亡。进一步检查发现，呼吸窘迫和肺不张发生在纯合子突变中。突变的Stk40(-/-)小鼠的肺和肺泡上皮成熟延迟，表现为肺内空气间隙变窄、间质间隔增厚和糖原含量增加。T1-α、SP-B和SP-C水平的降低表明Stk40(-/-)肺中I型和II型呼吸道上皮细胞成熟延迟。此外，在所有被测试的器官中，Stk40在胎鼠和成年鼠的肺中表达最高。从机理上讲，全基因组RNA微阵列分析显示，参与肺发育的多个已知基因的表达发生了显著变化。在Stk40(-/-)小鼠的肺中，参与脂肪代谢、免疫反应和糖原代谢的一些基因的表达也被破坏。蛋白质亲和纯化鉴定ERK/MAPK信号通路激活物RCN2为STK40相关蛋白。Stk40缺乏可抑制肺上皮细胞ERK/MAPK活性，抑制ERK/MAPK活性可降低肺上皮细胞表面活性蛋白基因的表达。总而言之，这项研究揭示了STK40在肺成熟和新生儿存活中的重要作用。STK40可能与RCN2联合激活ERK/MAPK信号通路，调控肺发育的多个关键调节因子的表达。
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-alpha, 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 ofERK/MAPKsignaling, 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.