Teratogen-induced, dietary and genetic models of congenital diaphragmatic hernia share a common mechanism of pathogenesis.
Congenital diaphragmatic hernia (CDH) is a frequently occurring, major congenital abnormality that has high mortality and significant morbidity in survivors. Currently, the pathogenesis of CDH is poorly understood. In this study, we have compared the anatomical characteristics of diaphragm defects in the well-described nitrofen model with the pathogenesis of CDH in vitamin A-deficient rats and wt1 null-mutant mice, representing teratogen-induced, dietary and genetic models of CDH, respectively. Our histological investigations, aided by three-dimensional reconstruction of the developing diaphragm, revealed a common pathogenic mechanism with regards to the location of the diaphragm defect in the foramen of Bochdalek (posterolateral diaphragm) and specific abnormalities within the primordial diaphragm. Furthermore, our analysis of postmortem specimens highlighted similarities in human cases of CDH and these animal models, supporting our hypothesis that CDH in humans arises from a defect in the primordial diaphragm. Immunohistochemical data were consistent with the defect in the primordial diaphragm being in the nonmuscular component. Importantly, these data show that very distinct models of CDH all share a common pathogenic mechanism and, together with supporting evidence from pathological specimens, highlight our proposed pathogenic model for CDH.
Clugston
Robin D
RD
Department of Physiology, University of Alberta, 513 HMRC, Edmonton, AB, Canada, T6G 2S2.
Klattig
Jürgen
J
Englert
Chistoph
C
Clagett-Dame
Margaret
M
Martinovic
Jelena
J
Benachi
Alexandra
A
Greer
John J
JJ
D000818:Animals; D051837:COUP Transcription Factor II / Q000378:metabolism; D003964:Diaphragm / Q000002:abnormalities / Q000196:embryology; D004032:Diet; D004195:Disease Models, Animal; D005260:Female; D005333:Fetus / Q000002:abnormalities; D006548:Hernia, Diaphragmatic / Q000139:chemically induced* / Q000473:pathology*; D006801:Humans; D007223:Infant; D051379:Mice; D008810:Mice, Inbred C57BL; D008957:Models, Genetic; D009132:Muscles / Q000166:cytology / Q000473:pathology; D009154:Mutation / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013723:Teratogens; D014802:Vitamin A Deficiency; D025721:WT1 Proteins / Q000378:metabolism
D051837:COUP Transcription Factor II; D013723:Teratogens; D025721:WT1 Proteins