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Eur J Pediatr Surg

Title:		"Pbx1, Meis1, and Runx1 Expression Is Decreased in the Diaphragmatic and Pulmonary Mesenchyme of Rats with Nitrofen-Induced Congenital Diaphragmatic Hernia"
Author(s):		Takahashi T; Friedmacher F; Zimmer J; Puri P;
Address:		"National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland. Department of Pediatric Surgery, Kansai Medical University, Osaka, Japan. Department of Pediatric Surgery, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main, Germany. Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany. Beacon Hospital, University College Dublin, Dublin, Ireland"
Journal Title:		Eur J Pediatr Surg
Year:		2021
Volume:		20200830
Issue:		1
Page Number:		120 - 125
DOI:		10.1055/s-0040-1714736
ISSN/ISBN:		1439-359X (Electronic) 0939-7248 (Linking)
Abstract:		"INTRODUCTION: Congenital diaphragmatic hernia (CDH) and associated pulmonary hypoplasia (PH) are thought to originate from mesenchymal defects in pleuroperitoneal folds (PPFs) and primordial lungs. Pre-B-cell leukemia homeobox 1 (Pbx1), its binding partner myeloid ecotropic integration site 1 (Meis1), and runt-related transcription factor 1 (Runx1) are expressed in diaphragmatic and lung mesenchyme, functioning as transcription cofactors that modulate mesenchymal cell proliferation. Furthermore, Pbx1 (-/-) mice develop diaphragmatic defects and PH similar to human CDH. We hypothesized that diaphragmatic and pulmonary Pbx1, Meis1, and Runx1 expression is decreased in the nitrofen-induced CDH model. MATERIALS AND METHODS: Time-mated rats were exposed to nitrofen or vehicle on gestational day 9 (D9). Fetal diaphragms (n = 72) and lungs (n = 48) were microdissected on D13, D15, and D18, and were divided into control and nitrofen-exposed specimens. Diaphragmatic and pulmonary gene expression levels of Pbx1, Meis1, and Runx1 were analyzed by quantitative real-time polymerase chain reaction. Immunofluorescence-double-staining for Pbx1, Meis1, and Runx1 was combined with mesenchymal/myogenic markers Gata4 and myogenin to evaluate protein expression. RESULTS: Relative mRNA expression of Pbx1, Meis1, and Runx1 was significantly decreased in PPFs (D13), developing diaphragms/lungs (D15), and muscularized diaphragms/differentiated lungs (D18) of nitrofen-exposed fetuses compared with controls. Confocal-laser-scanning-microscopy revealed markedly diminished Pbx1, Meis1, and Runx1 immunofluorescence in diaphragmatic and pulmonary mesenchyme, associated with less proliferating mesenchymal cells in nitrofen-exposed fetuses on D13, D15, and D18 compared with controls. CONCLUSION: Decreased Pbx1, Meis1, and Runx1 expression during diaphragmatic development and lung branching morphogenesis may reduce mesenchymal cell proliferation, causing malformed PPFs and disrupted airway branching, thus leading to diaphragmatic defects and PH in the nitrofen-induced CDH model"
Keywords:		"Animals Core Binding Factor Alpha 2 Subunit Diaphragm/embryology/*metabolism Disease Models, Animal Female Gene Expression Regulation, Developmental Hernia, Diaphragmatic/embryology/genetics/*metabolism Humans Lung/embryology/*metabolism Male Mesoderm/met;"
Notes:		"MedlineTakahashi, Toshiaki Friedmacher, Florian Zimmer, Julia Puri, Prem eng 2020/08/31 Eur J Pediatr Surg. 2021 Feb; 31(1):120-125. doi: 10.1055/s-0040-1714736. Epub 2020 Aug 30"