Molecular mechanisms of early lung specification and branching morphogenesis.
The "hard wiring" encoded within the genome that determines the emergence of the laryngotracheal groove and subsequently early lung branching morphogenesis is mediated by finely regulated, interactive growth factor signaling mechanisms that determine the automaticity of branching, interbranch length, stereotypy of branching, left-right asymmetry, and finally gas diffusion surface area. The extracellular matrix is an important regulator as well as a target for growth factor signaling in lung branching morphogenesis and alveolarization. Coordination not only of epithelial but also endothelial branching morphogenesis determines bronchial branching and the eventual alveolar-capillary interface. Improved prospects for lung protection, repair, regeneration, and engineering will depend on more detailed understanding of these processes. Herein, we concisely review the functionally integrated morphogenetic signaling network comprising the critical bone morphogenetic protein, fibroblast growth factor, Sonic hedgehog, transforming growth factor-beta, vascular endothelial growth factor, and Wnt signaling pathways that specify and drive early embryonic lung morphogenesis.
Warburton
David
D
Developmental Biology Program, The Saban Research Institute of Childrens Hospital Los Angeles, CA 90027, USA. dwarburton@chla.usc.edu
Bellusci
Saverio
S
De Langhe
Stijn
S
Del Moral
Pierre-Marie
PM
Fleury
Vincent
V
Mailleux
Arnaud
A
Tefft
Denise
D
Unbekandt
Mathieu
M
Wang
Kasper
K
Shi
Wei
W
D000818:Animals; D019070:Cell Lineage; D004330:Drosophila; D004848:Epithelium / Q000378:metabolism; D004947:Esophagus / Q000473:pathology; D005346:Fibroblast Growth Factors / Q000096:biosynthesis; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D007830:Larynx / Q000378:metabolism; D008024:Ligands; D008168:Lung / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D009154:Mutation; D018919:Neovascularization, Physiologic; D010455:Peptides / Q000737:chemistry; D020033:Protein Isoforms; D015398:Signal Transduction; D014132:Trachea / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D051153:Wnt Proteins
D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D010455:Peptides; D020033:Protein Isoforms; C509239:SHH protein, human; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D051153:Wnt Proteins; D005346:Fibroblast Growth Factors