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01.11.2013 | Original Article

Expression of Sproutys and SPREDs is decreased during lung branching morphogenesis in nitrofen-induced pulmonary hypoplasia

verfasst von: Florian Friedmacher, Jan-Hendrik Gosemann, Naho Fujiwara, Hiromizu Takahashi, Alejandro Hofmann, Prem Puri

Erschienen in: Pediatric Surgery International | Ausgabe 11/2013

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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.

Loane M, Dolk H, Kelly A et al (2011) EUROCAT statistical monitoring: identification and investigation of ten year trends of congenital anomalies in Europe. Birth Defects Res A Clin Mol Teratol 91(Suppl 1):S31–S43PubMedCrossRef

Vergani P (2012) Prenatal diagnosis of pulmonary hypoplasia. Curr Opin Obstet Gynecol 24(2):89–94PubMedCrossRef

Gaxiola A, Varon J, Valladolid G (2009) Congenital diaphragmatic hernia: an overview of the etiology and current management. Acta Paediatr 98(4):621–627PubMedCrossRef

Keijzer R, Puri P (2010) Congenital diaphragmatic hernia. Semin Pediatr Surg 19(3):180–185PubMedCrossRef

van Loenhout RB, Tibboel D, Post M et al (2009) Congenital diaphragmatic hernia: comparison of animal models and relevance to the human situation. Neonatology 96(3):137–149PubMedCrossRef

Beurskens N, Klaassens M, Rottier R et al (2007) Linking animal models to human congenital diaphragmatic hernia. Birth Defects Res A Clin Mol Teratol 79(8):565–572PubMedCrossRef

Montedonico S, Nakazawa N, Puri P (2008) Congenital diaphragmatic hernia and retinoids: searching for an etiology. Pediatr Surg Int 24(7):755–761PubMedCrossRef

Roth-Kleiner M, Post M (2003) Genetic control of lung development. Biol Neonate 84(1):83–88PubMedCrossRef

Roth-Kleiner M, Post M (2005) Similarities and dissimilarities of branching and septation during lung development. Pediatr Pulmonol 40(2):113–134PubMedCrossRef

10.

Moura RS, Coutinho-Borges JP, Pacheco AP et al (2011) FGF signaling pathway in the developing chick lung: expression and inhibition studies. PLoS ONE 6(3):e17660PubMedCrossRef

11.

Hashimoto S, Nakano H, Singh G et al (2002) Expression of Spred and Sprouty in developing rat lung. Mech Dev 119(Suppl 1):S303–S309PubMedCrossRef

12.

Zhang S, Lin Y, Itaranta P et al (2001) Expression of Sprouty genes 1, 2 and 4 during mouse organogenesis. Mech Dev 109(2):367–370PubMedCrossRef

13.

Taniguchi K, Ayada T, Ichiyama K et al (2007) Sprouty2 and Sprouty4 are essential for embryonic morphogenesis and regulation of FGF signaling. Biochem Biophys Res Commun 352(4):896–902PubMedCrossRef

14.

Engelhardt CM, Bundschu K, Messerschmitt M et al (2004) Expression and subcellular localization of Spred proteins in mouse and human tissues. Histochem Cell Biol 122(6):527–538PubMedCrossRef

15.

Miura T (2008) Modeling lung branching morphogenesis. Curr Top Dev Biol 81:291–310PubMedCrossRef

16.

Short K, Hodson M, Smyth I (2013) Spatial mapping and quantification of developmental branching morphogenesis. Development 140(2):471–478PubMedCrossRef

17.

Han RN, Liu J, Tanswell AK et al (1992) Expression of basic fibroblast growth factor and receptor: immunolocalization studies in developing rat fetal lung. Pediatr Res 31(5):435–440PubMedCrossRef

18.

Friedmacher F, Doi T, Gosemann JH et al (2012) Upregulation of fibroblast growth factor receptor 2 and 3 in the late stages of fetal lung development in the nitrofen rat model. Pediatr Surg Int 28(2):195–199PubMedCrossRef

19.

Friedmacher F, Gosemann JH, Takahashi H et al (2013) Decreased pulmonary c-Cbl expression and tyrosine phosphorylation in the nitrofen-induced rat model of congenital diaphragmatic hernia. Pediatr Surg Int 29(1):19–24PubMedCrossRef

20.

Bundschu K, Walter U, Schuh K (2007) Getting a first clue about SPRED functions. BioEssays 29(9):897–907PubMedCrossRef

Titel: Expression of Sproutys and SPREDs is decreased during lung branching morphogenesis in nitrofen-induced pulmonary hypoplasia
verfasst von: Florian Friedmacher
Jan-Hendrik Gosemann
Naho Fujiwara
Hiromizu Takahashi
Alejandro Hofmann
Prem Puri
Publikationsdatum: 01.11.2013
Verlag: Springer Berlin Heidelberg
Erschienen in: Pediatric Surgery International / Ausgabe 11/2013
Print ISSN: 0179-0358
Elektronische ISSN: 1437-9813
DOI: https://doi.org/10.1007/s00383-013-3385-6

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Expression of Sproutys and SPREDs is decreased during lung branching morphogenesis in nitrofen-induced pulmonary hypoplasia