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Updated: Apr 15, 2026
Transuterine Fetal Tracheal Occlusion Model in Mice
Published on: February 5, 2021
Muscle connective tissue controls development of the diaphragm and is a source of congenital diaphragmatic hernias
Allyson J Merrell1, Benjamin J Ellis2, Zachary D Fox1
1Department of Human Genetics, University of Utah, Salt Lake City, Utah, USA.
Insights
Congenital diaphragmatic hernias (CDHs) stem from developmental defects. This study reveals transient embryonic structures called pleuroperitoneal folds (PPFs) are crucial for diaphragm muscle development and that mutations in their derived cells cause CDH.
Area of Science:
- Developmental biology
- Mammalian embryogenesis
- Musculoskeletal development
Background:
- Congenital diaphragmatic hernias (CDHs) are common, often lethal birth defects caused by diaphragm developmental errors.
- The embryonic origins and cellular mechanisms driving diaphragm formation remain largely unknown.
- Despite identifying CDH-associated genes, the precise etiology of CDH is incompletely understood.
Purpose of the Study:
- To elucidate the embryonic source of diaphragm muscle connective tissue.
- To investigate the role of specific embryonic structures in diaphragm development and morphogenesis.
- To identify cellular mechanisms linking genetic mutations to CDH pathogenesis.
Main Methods:
- Utilized mouse genetics to trace embryonic cell lineages and study gene function.
- Investigated the migration patterns and developmental roles of pleuroperitoneal fold (PPF) cells.
- Analyzed the impact of Gata4 mosaic mutations in PPF-derived fibroblasts on diaphragm structure and function.
Main Results:
- Identified pleuroperitoneal folds (PPFs) as the source of diaphragm muscle connective tissue.
- Demonstrated that PPF cell migration is critical for diaphragm morphogenesis.
- Showed that Gata4 mutations in PPF-derived fibroblasts lead to amuscular regions and CDH.
Conclusions:
- Pleuroperitoneal folds (PPFs) and their derived muscle connective tissue are essential for normal diaphragm development.
- Mutations within PPF-derived fibroblasts represent a significant source of congenital diaphragmatic hernias.
- Understanding PPF development offers new insights into CDH etiology and potential therapeutic targets.
Abstract:
The diaphragm is an essential mammalian skeletal muscle, and defects in diaphragm development are the cause of congenital diaphragmatic hernias (CDHs), a common and often lethal birth defect. The diaphragm is derived from multiple embryonic sources, but how these give rise to the diaphragm is unknown, and, despite the identification of many CDH-associated genes, the etiology of CDH is incompletely understood. Using mouse genetics, we show that the pleuroperitoneal folds (PPFs), which are transient embryonic structures, are the source of the diaphragm's muscle connective tissue and regulate muscle development, and we show that the striking migration of PPF cells controls diaphragm morphogenesis. Furthermore, Gata4 mosaic mutations in PPF-derived muscle connective tissue fibroblasts result in the development of localized amuscular regions that are biomechanically weaker and more compliant, leading to CDH. Thus, the PPFs and muscle connective tissue are critical for diaphragm development, and mutations in PPF-derived fibroblasts are a source of CDH.
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