Abstract
Congenital diaphragmatic hernia (CDH) is a severe birth defect. Wt1-null mouse embryos develop CDH but the mechanisms regulated by WT1 are unknown. We have generated a murine model with conditional deletion of WT1 in the lateral plate mesoderm, using the G2 enhancer of the Gata4 gene as a driver. 80% of G2-Gata4(Cre);Wt1(fl/fl) embryos developed typical Bochdalek-type CDH. We show that the posthepatic mesenchymal plate coelomic epithelium gives rise to a mesenchyme that populates the pleuroperitoneal folds isolating the pleural cavities before the migration of the somitic myoblasts. This process fails when Wt1 is deleted from this area. Mutant embryos show Raldh2 downregulation in the lateral mesoderm, but not in the intermediate mesoderm. The mutant phenotype was partially rescued by retinoic acid treatment of the pregnant females. Replacement of intermediate by lateral mesoderm recapitulates the evolutionary origin of the diaphragm in mammals. CDH might thus be viewed as an evolutionary atavism.
Highlights
Congenital diaphragmatic hernia (CDH) is a severe birth defect, characterized by incomplete formation or muscularization of the diaphragm and, as a consequence, herniation of the stomach, intestines, liver or spleen into the pulmonary cavities, leading to pulmonary hypoplasia
Our findings indicate that WT1 is involved in the generation of the mesenchyme of the septum transversum (ST)/posthepatic mesenchymal plate (PHMP)/pleuroperitoneal folds (PPFs) continuum through epithelial-mesenchymal transition and they provide a novel perspective on the genesis of the Bochdalek hernia and the evolutionary origin of the diaphragm
The liver partially detaches from this ST/PPF membrane, which becomes muscularized by migration of myoblasts from the somite
Summary
Congenital diaphragmatic hernia (CDH) is a severe birth defect, characterized by incomplete formation or muscularization of the diaphragm and, as a consequence, herniation of the stomach, intestines, liver or spleen into the pulmonary cavities, leading to pulmonary hypoplasia. Some authors describe that this fusion rather occurs with the posthepatic mesenchymal plate (PHMP), an accumulation of mesenchymal cells derived from the ST and located in the posterodorsal margin of the liver lobes (Iritani et al, 1984). All these tissues form an anatomical continuum, we will refer to the posterior, dorsolateral areas of the liver as PHMP, and PPFs to the tissue folds located in the dorsal part of the coelomic cavity, marking the limit between the peritoneal and the pleural cavities
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
