Journal
DEVELOPMENT
Volume 146, Issue 15, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.176354
Keywords
Pdgfra; Alveolar formation; Elastogenesis; Lung development; Secondary crest myofibroblast; Mouse; Human
Categories
Funding
- National Institutes of Health [HL122764, HL143059, HL144932, HL135747]
- Hastings Foundation
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL122764, R01HL144932, R01HL143059] Funding Source: NIH RePORTER
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Postnatal alveolar formation is the most important and the least understood phase of lung development. Alveolar pathologies are prominent in neonatal and adult lung diseases. The mechanisms of alveologenesis remain largely unknown. We inactivated Pdgfra postnatally in secondary crest myofibroblasts (SCMF), a subpopulation of lung mesenchymal cells. Lack of Pdgfra arrested alveologenesis akin to bronchopulmonary dysplasia (BPD), a neonatal chronic lung disease. The transcriptome of mutant SCMF revealed 1808 altered genes encoding transcription factors, signaling and extracellular matrix molecules. Elastin mRNA was reduced, and its distribution was abnormal. Absence of Pdgfra disrupted expression of elastogenic genes, including members of the Lox, Fbn and Fbln families. Expression of EGF family members increased when Tgfb1 was repressed in mouse. Similar, but not identical, results were found in human BPD lung samples. In vitro, blocking PDGF signaling decreased elastogenic gene expression associated with increased Egf and decreased Tgfb family mRNAs. The effect was reversible by inhibiting EGF or activating TGF beta signaling. These observations demonstrate the previously unappreciated postnatal role of PDGFA/PDGFR alpha in controlling elastogenic gene expression via a secondary tier of signaling networks composed of EGF and TGF beta.
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