Figure 5

Morphogenetic "Turing" gradients and some of their major regulators in murine early airway branching. This conceptual figure shows some of the key morphogens and their major regulators diagramed as putative "Turing" gradients, within a branching early embryonic mouse lung lobe. In the bottom panel, both lateral (monopodial) and terminal (dipodial) epithelial branches are diagramed, within a coating of mesenchyme and pleura. In the 5 panels shown above this one, concentrations or activities of key morphogens and their respective regulator molecules are shown as arbitrary relative expression/activity "Turing" gradients. In the top panel Fibroblast Growth Factor10 (FGF10) is shown as a solid line. The FGF10 "Turing" gradient is highest near the pleura and its concentration/activity gradient decays through the peripheral mesenchyme and forms an asymmetrical gradient across the distal bipodial branch induction domain. FGF10 then remains low until it peaks once more within the proximal monopodial branch induction domain. The expression/activity of mSPRY2, shown as the dotted line, is induced by FGF10 within the epithelial branch tips. In contrast, the expression/activity of mSPRY4 peaks in the peripheral mesenchyme and in the mesenchyme between the branch tips. The net result is that FGF10 expression/activity is powerfully negatively regulated between branches, but is increased within branch tips. FGF10 expression/activity is symmetrical within monopodial branch tips, but within dipodial distal tips it is asymmetrical. We suggest that the relative symmetry of the FGF10 expression/activity "Turing" gradient may play a key role in determining whether a specific branch will be mono or dipodial. Also the relative activity of FGF10 and mSPRY2 may play a key role in determining interbranch length and setting up subsequent branch points. In the second panel, SHH is shown as the hatched line and HIP is shown as the solid line. The sharp induction of Hedghog Interacting Protein (HIP) within the branch tips serves to inhibit Sonic hedghog (SHH) expression/activity. As noted in the text, SHH expression/activity is highest in between branch tips, i.e. in places where branches are not supposed to occur. SHH likely plays a major role in negatively regulating FGF10 expression/activity at these inter-branch sites. Conversely, negative regulation of SHH expression/activity by HIP may facilitate FGF10 expression/activity at points where branches are genetically programmed to arise. In the third panel, Bone Morphogenetic Protein4 (BMP4) expression/activity is shown as the solid line. BMP4 expression/activity is relatively low between branches but is increased at branch tips. The activity/expression of Noggin, shown as the dotted line, is the inverse of BMP4. Noggin expression/activity is high between branches and low at branch tips. Gremlin expression/activity is shown as the hatched line. Gremlin follows the contour of BMP4. Thus, the net BMP4 concentration/activity "Turing" gradient peaks in branch tips and is relatively suppressed between them. BMP4 signaling elements however show a more complicated picture. In the fourth panel BMP Smads 1 and 5 concentration/activities are shown. Smad1 peaks within branch tips and is low between them. Smad 5 on the other hand is expressed within small clusters of cells out in the mesenchyme. In the fifth panel, Transforming Growth Factorβ 2 (TGFβ 2) is shown as the solid line, while its signaling Smads 2, 3 and 4 are shown together as the hatched line. TGFβ 2 expression/activity is quite widespread throughout both mesenchyme and epithelium, but peaks within branch tips. Smads 2, 3 and 4 peak within branch tips. Therefore it is likely that TGFβ 2 only signals to any significant extent within branch tips. We suggest that morphogenesis of the branching airway is determined by genes responding to the hard wired temporospatial net integration of the "Turing" gradient distribution of the above morphogens and probably others as well. This conceptual framework represents our latest model for considering this hypothesis.