| First Author | Lai YT | Year | 2020 |
| Journal | J Biomed Sci | Volume | 27 |
| Issue | 1 | Pages | 52 |
| PubMed ID | 32295602 | Mgi Jnum | J:298056 |
| Mgi Id | MGI:6457190 | Doi | 10.1186/s12929-020-00643-0 |
| Citation | Lai YT, et al. (2020) CPEB2-activated PDGFRalpha mRNA translation contributes to myofibroblast proliferation and pulmonary alveologenesis. J Biomed Sci 27(1):52 |
| abstractText | BACKGROUND: 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 alpha (PDGFRalpha) signaling is crucial for alveolar myofibroblast (MYF) proliferation and its deficiency is associated with risk of BPD, but posttranscriptional mechanisms regulating PDGFRalpha 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. METHODS: 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 PDGFRalpha mRNA translation and MYF proliferation. RESULTS: 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 PDGFRalpha 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 PDGFRalpha expression was rescued by ectopic expression of CPEB2, suggesting an important role of CPEB2 in upregulating PDGFRalpha signaling for pulmonary alveologenesis. CONCLUSIONS: CPEB2-controlled translation, in part through promoting PDGFRalpha 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. |
