Abstract
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.
Highlights
Lung morphogenesis is stereotypic, both for lobation of the lungs and for the first 16 of 23 generations in humans
Murine genetics and organ culture experiments, as well as comparative studies in the fly, have revealed that the stereotypic branch pattern of the respiratory organs is determined by a well-conserved, genetically hard-wired program directed by transcriptional factors, that interact in a coordinated manner with peptide growth factor signaling pathways as well as hypoxia and physical forces [1,2,3,4]
Transduction of candidate growth factor peptide ligand signals can be regulated at many levels
Summary
Both for lobation of the lungs and for the first 16 of 23 generations in humans. The interactions of subsets of these ligand signals, SHH, BMP4 and FGF10 have been extensively reviewed recently and several models have been proposed to explain how they may interact to induce and regulate epithelial branching morphogenesis [1,2,3,5] These models propose that FGF10, which is expressed focally in embryonic lung mesenchyme adjacent to stereotypically determined branching sites, acts as a potent chemoattractant to epithelium. The role of ALK6 in pulmonary maturation was recently underscored by Weaver and coworkers, who showed that the BMP signaling mediated by these receptors regulates the proximal-distal differentiation of endoderm in mouse lung development [7]. This suggests that Lefty normally restricts Lefty-2 and Nodal expression to the left side, and that Lefty-2 or Nodal encode a signal for "leftness" in the lung [124]
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