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- Title
Expression of Sproutys and SPREDs is decreased during lung branching morphogenesis in nitrofen-induced pulmonary hypoplasia.
- Authors
Friedmacher, Florian; Gosemann, Jan-Hendrik; Fujiwara, Naho; Takahashi, Hiromizu; Hofmann, Alejandro; Puri, Prem
- Abstract
Purpose: Pulmonary hypoplasia (PH) is a life-threatening condition associated with congenital diaphragmatic hernia (CDH), characterized by defective lung development. Sproutys and Sprouty-related proteins (SPREDs) play a key role in lung branching morphogenesis through modification of epithelial-mesenchymal interactions. During the pseudoglandular stage, Sproutys are highly expressed in distal airway epithelium, while SPREDs within the surrounding mesenchyme. Sprouty2/4 knockouts show severe defects in branching morphogenesis with reduced number of distal airways. SPRED-1 and SPRED-2 are strongly expressed in regions of new airway formation, highlighting their important function in branching pattern. We hypothesized that expression of Sprouty2, Sprouty4, SPRED-1 and SPRED-2 is decreased during lung branching morphogenesis in nitrofen-induced PH. Methods: Timed-pregnant rats received either nitrofen or vehicle on E9.5. On E15.5 ( n = 16), fetal lungs were micro-dissected and divided into controls and PH, while on E18.5 ( n = 24) groups were: control, PH without CDH [CDH(−)], and PH with CDH [CDH(+)]. Pulmonary gene expression levels of Sprouty2, Sprouty4, SPRED- 1 and SPRED- 2 were analyzed by qRT-PCR. Immunohistochemistry was performed to evaluate protein expression/distribution. Results: On E18.5, relative mRNA expression levels of Sprouty2, Sprouty4, SPRED- 1 and SPRED- 2 were significantly decreased in CDH(−) and CDH(+) groups compared to controls ( P < 0.05). Immunoreactivity of Sprouty2, Sprouty4, SPRED-1 and SPRED-2 was markedly diminished on E18.5 in nitrofen-induced PH. Conclusion: Decreased expression of Sproutys and SPREDs during the terminal pseudoglandular stage may disrupt lung branching morphogenesis by interfering with epithelial-mesenchymal interactions contributing to PH.
- Subjects
PULMONARY hypoplasia; IMMUNOHISTOCHEMISTRY; NITROFEN; DROSOPHILA; MORPHOGENESIS; DIAPHRAGMATIC hernia; REVERSE transcriptase polymerase chain reaction
- Publication
Pediatric Surgery International, 2013, Vol 29, Issue 11, p1193
- ISSN
0179-0358
- Publication type
Article
- DOI
10.1007/s00383-013-3385-6