Abstract
The arborescent architecture of mammalian conductive airways results from the repeated branching of lung endoderm into surrounding mesoderm. Subsequent lung’s striking geometrical features have long raised the question of developmental mechanisms involved in morphogenesis. Many molecular actors have been identified, and several studies demonstrated the central role of Fgf10 and Shh in growth and branching. However, the actual branching mechanism and the way branching events are organized at the organ scale to achieve a self-avoiding tree remain to be understood through a model compatible with evidenced signaling. In this paper we show that the mere diffusion of FGF10 from distal mesenchyme involves differential epithelial proliferation that spontaneously leads to branching. Modeling FGF10 diffusion from sub-mesothelial mesenchyme where Fgf10 is known to be expressed and computing epithelial and mesenchymal growth in a coupled manner, we found that the resulting laplacian dynamics precisely accounts for the patterning of FGF10-induced genes, and that it spontaneously involves differential proliferation leading to a self-avoiding and space-filling tree, through mechanisms that we detail. The tree’s fine morphological features depend on the epithelial growth response to FGF10, underlain by the lung’s complex regulatory network. Notably, our results suggest that no branching information has to be encoded and that no master routine is required to organize branching events at the organ scale. Despite its simplicity, this model identifies key mechanisms of lung development, from branching to organ-scale organization, and could prove relevant to the development of other branched organs relying on similar pathways.
Highlights
Regulation of early lung development has been the subject of intensive research over the past few decades
There are no adjustable parameters since we directly solved Eq 2. Both Spry2 expression and FGF10 flux are focused on distal tips of the buds, and are very sensitive to local geometry, as shows the postbranching image (Fig. 3B) where both expression and flux are very low at the branching point
The same effect is observed: flux is spontaneously higher on distal tips (Fig. 4). This can be interpreted as a geometrical effect of FGF10 diffusion, since the resulting laplacian field and its gradient are dramatically sensitive to local distance to mesothelium and to local epithelium curvature
Summary
Regulation of early lung development has been the subject of intensive research over the past few decades. Bronchi never meet one another nor reach the pleural mesothelium enclosing the mesenchyme, which introduces a typical distance from distal buds to mesothelium These aspects of lung geometry are rarely considered in relevant literature or in developmental models [1,3,4], they are highly non-trivial in this confined geometry. Further analysis shows that Spry expression is up-regulated by FGF10 reception by epithelial FGFR2b, suggesting that FGF10 income concentrates on epithelial buds. These insights into molecular regulation of lung development have led to several genetic models [2,3]. No explicit mechanism has been proposed to account for the organ-scale organization
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