title: Embryological origins and development of the rat diaphragm.
abstract: Textbooks of embryology provide a standard set of drawings and text reflecting the traditional interpretation of phrenic nerve and diaphragm development based on anatomical dissections of embryonic tissue. Here, we revisit this issue, taking advantage of immunohistochemical markers for muscle precursors in conjunction with mouse mutants to perform a systematic examination of phrenic-diaphragm embryogenesis. This includes examining the spatiotemporal relationship of phrenic axon outgrowth and muscle precursors during different stages of myogenesis. Additionally, mutant mice lacking c-met receptors were used to visualize the mesenchymal substratum of the developing diaphragm in the absence of myogenic cells. We found no evidence for contributions to the diaphragm musculature from the lateral body wall, septum transversum, or esophageal mesenchyme, as standard dogma would state. Nor did the data support the hypothesis that the crural diaphragm is of distinct embryological origins. Rather, we found that myogenic cells and axons destined to form the neuromuscular component of the diaphragm coalesce within the pleuroperitoneal fold (PPF). It is the expansion of these components of the PPF that leads to the formation of the diaphragm. Furthermore, we extended these studies to examine the developing diaphragm in an animal model of congenital diaphragmatic hernia (CDH). We find that malformation of the PPF mesenchymal substratum leads to the defect characteristic of CDH. In summary, the data demonstrates that a significant revision of narratives describing normal and pathological development of the diaphragm is warranted.
authors.affiliation: Department of Physiology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
authors.forename: Randal P
authors.initials: RP
authors.lastname: Babiuk
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Robin
authors.initials: R
authors.lastname: Clugston
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Allan
authors.forename: John J
authors.initials: JJ
authors.lastname: Greer
mesh_terms: D000818:Animals; D002455:Cell Division; D002465:Cell Movement; D003964:Diaphragm / Q000002:abnormalities* / Q000294:innervation / Q000473:pathology; D004195:Disease Models, Animal; D006548:Hernia, Diaphragmatic / Q000139:chemically induced / Q000473:pathology*; D065630:Hernias, Diaphragmatic, Congenital; D051379:Mice; D024510:Muscle Development; D018485:Muscle Fibers, Skeletal / Q000166:cytology; D010647:Phenyl Ethers; D010791:Phrenic Nerve / Q000166:cytology / Q000196:embryology*; D019859:Proto-Oncogene Proteins c-met / Q000172:deficiency / Q000235:genetics; D051381:Rats; D015619:Respiratory System Abnormalities / Q000235:genetics / Q000473:pathology*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D010647:Phenyl Ethers; D019859:Proto-Oncogene Proteins c-met; C007350:nitrofen