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The molecular genetics of lung morphogenesis and injury repair
David Warburton1, Saverio Bellusci
1Developmental Biology Program, Saban Research Institute, Childrens Hospital Los Angeles, Los Angeles, California 90027, USA. dwarburton@chla.usc.edu
Abstract:
Lung development, as well as epithelial injury repair, is tightly coordinated by a fine balance between stimulatory versus inhibitory genes that appear to co-regulate the function of stem/progenitor cells in the lung. Recently, it has been noted that many of the same genes direct development of the respiratory organs (tracheae) in the fruit fly Drosophila as in mice and men. For example, FGF receptor tyrosine kinase signaling is essential for respiratory organogenesis in both fly and mouse and is negatively regulated by the sprouty genes, a family of inducible FGF pathway inhibitors. Additionally, FGF signaling is required for formation of new alveoli, protection of alveolar epithelial cells from injury, as well as migration and proliferation of putative alveolar stem/progenitor cells during lung repair. Conversely, TGFbeta receptor serine-threonine kinase signaling via Smads 2, 3 and 4 inhibits lung morphogenesis and can inhibit postnatal alveolar development, while excessive TGFbeta signaling via Smad3 causes interstitial fibrosis. On the other hand, BMP4 stimulates morphogenesis of intact embryonic lung, while inhibiting proliferation of isolated epithelium. We speculate that evolutionary-developmental, functional conservation of the FGF- FGFR-SPROUTY stimulatory pathway as well as of the TGFbeta/BMP-SMAD modulatory pathways identifies them as potential therapeutic targets for rational therapy. Novel therapy to activate lung stem/progenitor cells, ameliorate lung injury, augment lung repair and/or induce lung regeneration could be highly beneficial in both children and adults with intractable pulmonary insufficiency.
Insights
Genes controlling lung development and repair, like FGF and TGFbeta, are conserved across species. Understanding these pathways could lead to new therapies for lung injury and insufficiency.
Area of Science:
- Developmental Biology
- Regenerative Medicine
- Comparative Genomics
Background:
- Lung development and repair rely on a balance of stimulatory and inhibitory genes.
- Genes involved in fruit fly respiratory organ development are conserved in mammals.
- Fibroblast Growth Factor (FGF) and Transforming Growth Factor-beta (TGFbeta) signaling pathways play critical roles.
Purpose of the Study:
- To investigate the conserved roles of FGF and TGFbeta signaling pathways in lung development and repair.
- To explore the potential of these pathways as therapeutic targets for lung diseases.
Main Methods:
- Comparative analysis of gene function in Drosophila and mammalian lung development.
- Examination of FGF receptor tyrosine kinase signaling and its regulation by sprouty genes.
- Investigation of TGFbeta and Bone Morphogenetic Protein 4 (BMP4) signaling via Smad proteins.
Main Results:
- FGF signaling is crucial for respiratory organogenesis, alveolar formation, and stem/progenitor cell function during lung repair.
- TGFbeta signaling inhibits lung morphogenesis and postnatal alveolar development, with excessive signaling leading to fibrosis.
- BMP4 stimulates embryonic lung morphogenesis but inhibits isolated epithelial cell proliferation.
Conclusions:
- The evolutionary-developmental conservation of FGF-FGFR-SPROUTY and TGFbeta/BMP-SMAD pathways highlights their therapeutic potential.
- Targeting these pathways could lead to novel therapies for activating lung stem cells, promoting repair, and inducing regeneration.
- These approaches may benefit both children and adults with severe lung insufficiency.
