Alveologenesis is the final stage of lung development to form air-exchanging units between alveoli and blood vessels. Genetic susceptibility or hyperoxic stress to perturb this complicated process can cause abnormal enlargement of alveoli and lead to bronchopulmonary dysplasia (BPD)-associated emphysema. Platelet-derived growth factor receptor α (PDGFRα) signaling is crucial for alveolar myofibroblast (MYF) proliferation and its deficiency is associated with risk of BPD, but posttranscriptional mechanisms regulating PDGFRα synthesis during lung development remain largely unexplored. Cytoplasmic polyadenylation element-binding protein 2 (CPEB2) is a sequence-specific RNA-binding protein and translational regulator. Because CPEB2-knockout (KO) mice showed emphysematous phenotypes, we investigated how CPEB2-controlled translation affects pulmonary development and function. Respiratory and pulmonary functions were measured by whole-body and invasive plethysmography. Histological staining and immunohistochemistry were used to analyze morphology, proliferation, apoptosis and cell densities from postnatal to adult lungs. Western blotting, RNA-immunoprecipitation, reporter assay, primary MYF culture and ectopic expression rescue were performed to demonstrate the role of CPEB2 in PDGFRα mRNA translation and MYF proliferation. Adult CPEB2-KO mice showed emphysema-like dysfunction. The alveolar structure in CPEB2-deficient lungs appeared normal at birth but became simplified through the alveolar stage of lung development. In CPEB2-null mice, we found reduced proliferation of MYF progenitors during alveolarization, abnormal deposition of elastin and failure of alveolar septum formation, thereby leading to enlarged pulmonary alveoli. We identified that CPEB2 promoted PDGFRα mRNA translation in MYF progenitors and this positive regulation could be disrupted by H2O2, a hyperoxia-mimetic treatment. Moreover, decreased proliferating ability in KO MYFs due to insufficient PDGFRα expression was rescued by ectopic expression of CPEB2, suggesting an important role of CPEB2 in upregulating PDGFRα signaling for pulmonary alveologenesis. CPEB2-controlled translation, in part through promoting PDGFRα expression, is indispensable for lung development and function. Since defective pulmonary PDGFR signaling is a key feature of human BPD, CPEB2 may be a risk factor for BPD.

中文翻译：

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CPEB2激活的PDGFRαmRNA翻译有助于成肌纤维细胞增殖和肺泡形成

肺泡形成是肺发育的最后阶段，在肺泡和血管之间形成空气交换单位。遗传易感性或高氧应激会扰乱这个复杂的过程，可能导致肺泡异常增大并导致支气管肺发育不良（BPD）相关的肺气肿。血小板衍生的生长因子受体α（PDGFRα）信号对于肺泡成肌纤维细胞（MYF）的增殖至关重要，其缺乏与BPD的风险有关，但是在肺发育过程中调节PDGFRα合成的转录后机制仍未开发。细胞质聚腺苷酸化元素结合蛋白2（CPEB2）是一种序列特异性RNA结合蛋白和翻译调节因子。因为CPEB2基因敲除（KO）小鼠表现出气肿性表型，我们研究了CPEB2控制的翻译如何影响肺发育和功能。呼吸和肺功能通过全身和侵入性体积描记法进行测量。使用组织学染色和免疫组织化学分析从产后到成年肺的形态，增殖，凋亡和细胞密度。进行了蛋白质印迹，RNA免疫沉淀，报告基因分析，原代MYF培养和异位表达拯救，以证明CPEB2在PDGFRαmRNA翻译和MYF增殖中的作用。成年CPEB2-KO小鼠表现出肺气肿样功能障碍。CPEB2缺陷型肺中的肺泡结构在出生时看起来正常，但在肺部发育的肺泡阶段变得简化。在CPEB2空小鼠中，我们发现肺泡化过程中MYF祖细胞的增殖减少，弹性蛋白的异常沉积和肺泡间隔形成的失败，从而导致肺泡增大。我们发现CPEB2促进MYF祖细胞中PDGFRαmRNA的翻译，而这种高水平的正调节作用可能会被过氧模拟疗法H2O2破坏。此外，CPEB2的异位表达挽救了由于PDGFRα表达不足而导致的MY MYs增殖能力下降，提示CPEB2在上调PDGFRα肺泡生成信号中的重要作用。CPEB2控制的翻译（部分通过促进PDGFRα表达）对于肺部发育和功能不可或缺。由于有缺陷的肺PDGFR信号传导是人类BPD的关键特征，因此CPEB2可能是BPD的危险因素。我们发现CPEB2促进MYF祖细胞中PDGFRαmRNA的翻译，而这种高水平的正调节作用可能会被过氧模拟疗法H2O2破坏。此外，CPPD2的异位表达挽救了由于PDGFRα表达不足而导致的MY MYs增殖能力降低，提示CPEB2在上调PDGFRα肺泡生成信号中的重要作用。CPEB2控制的翻译（部分通过促进PDGFRα表达）对于肺部发育和功能不可或缺。由于有缺陷的肺PDGFR信号传导是人类BPD的关键特征，因此CPEB2可能是BPD的危险因素。我们发现CPEB2促进MYF祖细胞中PDGFRαmRNA的翻译，而这种高水平的正调节作用可能会被过氧模拟疗法H2O2破坏。此外，CPEB2的异位表达挽救了由于PDGFRα表达不足而导致的MY MYs增殖能力下降，提示CPEB2在上调PDGFRα肺泡生成信号中的重要作用。CPEB2控制的翻译（部分通过促进PDGFRα表达）对于肺部发育和功能不可或缺。由于有缺陷的肺PDGFR信号传导是人类BPD的关键特征，因此CPEB2可能是BPD的危险因素。CPEB2的异位表达可以挽救由于PDGFRα表达不足而导致的MY MYs增殖能力下降，提示CPEB2在上调PDGFRα肺泡生成信号中的重要作用。CPEB2控制的翻译（部分通过促进PDGFRα表达）对于肺部发育和功能不可或缺。由于有缺陷的肺PDGFR信号传导是人类BPD的关键特征，因此CPEB2可能是BPD的危险因素。CPEB2的异位表达挽救了由于PDGFRα表达不足而导致的MY MYs增殖能力降低，提示CPEB2在上调PDGFRα信号引起肺泡形成中的重要作用。CPEB2控制的翻译（部分通过促进PDGFRα表达）对于肺部发育和功能不可或缺。由于有缺陷的肺PDGFR信号传导是人类BPD的关键特征，因此CPEB2可能是BPD的危险因素。