Growth factor signaling in lung morphogenetic centers: automaticity, stereotypy and symmetry.
Lung morphogenesis is stereotypic, both for lobation and for the first several generations of airways, implying mechanistic control by a well conserved, genetically hardwired developmental program. This program is not only directed by transcriptional factors and peptide growth factor signaling, but also co-opts and is modulated by physical forces. Peptide growth factors signal within repeating epithelial-mesenchymal temporospatial patterns that constitute morphogenetic centers, automatically directing millions of repetitive events during both stereotypic branching and nonstereotypic branching as well as alveolar surface expansion phases of lung development. Transduction of peptide growth factor signaling within these centers is finely regulated at multiple levels. These may include ligand expression, proteolytic activation of latent ligand, ligand bioavailability, ligand binding proteins and receptor affinity and presentation, receptor complex assembly and kinase activation, phosphorylation and activation of adapter and messenger protein complexes as well as downstream events and cross-talk both inside and outside the nucleus. Herein we review the critical Sonic Hedgehog, Fibroblast Growth Factor, Bone Morphogenetic Protein, Vascular Endothelial Growth Factor and Transforming Growth Factorbeta signaling pathways and propose how they may be functionally coordinated within compound, highly regulated morphogenetic gradients that drive first stereotypic and then non-stereotypic, automatically repetitive, symmetrical as well as asymmetrical branching events in the lung.
Warburton
David
D
Developmental Biology Program, Childrens Hospital Los Angeles Research Institute and the Center for Craniofacial Molecular Biology, Keck School of Medicine and School of Dentistry, University of Southern California, USA. dwarburton@chla.usc.edu
Bellusci
Saverio
S
Del Moral
Pierre-Marie
PM
Kaartinen
Vesa
V
Lee
Matt
M
Tefft
Denise
D
Shi
Wei
W
D000375:Aging / Q000378:metabolism; D000818:Animals; D004622:Embryo, Mammalian / Q000378:metabolism; D004625:Embryo, Nonmammalian; D047108:Embryonic Development; D006133:Growth Substances / Q000378:metabolism*; D008168:Lung / Q000196:embryology* / Q000254:growth & development* / Q000378:metabolism; D015398:Signal Transduction
D006133:Growth Substances