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Current concepts on lung development
1Childrens Hospital Los Angeles Research Institute, CA 90027, USA. dwarburton@chlais.usc.edu
Abstract:
Recent molecular genetic and embryonic organ culture studies have implicated several novel regulatory processes in the coordination of lung development. Failure of pulmonary initiation results from interruptions of the sonic hedgehog/patched/Gli and Nkx 2.1 signaling pathways. Sonic hedgehog null mutants and Gli2/Gli3 compound null mutants each exhibited failed tracheoesophageal septation. However, proximodistal epithelial differentiation is disrupted by compound Gli mutation, but is preserved in sonic hedgehog mutants. Null mutation of Nkx 2.1 also abrogates tracheoesophageal septation in association with thyroid and pituitary agenesis. Primary tracheal branching is regulated by fibroblast growth factor-10 signaling; in the murine fibroblast growth factor-10 null phenotype, the lung fails to separate from the foregut and morphogenesis is arrested distal to the trachea. Several genes in the fibroblast growth factor-10 pathway have homologous roles in fruit fly tracheal organogenesis, and corresponding Drosophila mutations yield strikingly similar phenotypes. Recent data also indicate that airway branching can be regulated by vascular endothelial growth factor, suggesting mutual regulation of airway and vascular development. The bases of pulmonary left-right asymmetry and laterality have also been investigated. The transforming growth factor-beta superfamily members Lefty-1, Lefty-2, and nodal comprise a regulatory pathway whose function is required for the development of left-right asymmetry, whereas left-right laterality is dependent on regulation of dynein expression by the transcription factor hepatocyte nuclear factor-4. Terminal lung differentiation is modulated by yet another set of signals. Hoxa5 null mutants exhibit tracheal occlusion and surfactant protein deficiency, whereas fibroblast growth factor receptor-2 and -4 compound null phenotypes include abrogated neonatal alveolization, perturbed alveolar myofibroblast differentiation, and persistent neonatal elastin deposition. These new contributions represent substantial advances toward a comprehensive molecular model of pulmonary development.
Insights
Key signaling pathways like sonic hedgehog and fibroblast growth factor-10 are crucial for lung development, regulating everything from septation to branching and differentiation. Disruptions lead to severe developmental defects.
Area of Science:
- Developmental Biology
- Molecular Genetics
- Pulmonary Medicine
Background:
- Lung development involves complex molecular genetic regulation.
- Novel regulatory processes are increasingly implicated in coordinating lung formation.
- Understanding these pathways is critical for addressing congenital lung diseases.
Purpose of the Study:
- To elucidate the roles of specific signaling pathways in lung development.
- To investigate the genetic basis of pulmonary initiation, branching, and differentiation.
- To establish a comprehensive molecular model of pulmonary development.
Main Methods:
- Molecular genetic studies in model organisms (e.g., mice, fruit flies).
- Embryonic organ culture techniques.
- Analysis of null and compound null mutant phenotypes.
Main Results:
- Sonic hedgehog/patched/Gli and Nkx 2.1 pathways are essential for pulmonary initiation and tracheoesophageal septation.
- Fibroblast growth factor-10 signaling regulates primary tracheal branching and lung separation from the foregut.
- Transforming growth factor-beta superfamily members (Lefty-1, Lefty-2, nodal) and transcription factors (HNF-4) control lung asymmetry and laterality.
- Hoxa5, FGFR2, and FGFR4 mutations impact terminal lung differentiation, alveolization, and surfactant production.
Conclusions:
- Specific molecular pathways, including sonic hedgehog, FGF10, and TGF-beta superfamily members, are indispensable for normal lung development.
- Genetic disruptions in these pathways lead to a spectrum of congenital pulmonary abnormalities.
- These findings advance the development of a comprehensive molecular model for pulmonary morphogenesis.