FIGURE 2.

Regulation principles of branching hallmarks in lung and kidney morphogenesis. (A) Branching modes used by lungs and kidneys. Lateral branches in the lung are oriented at an angle of around 80°. In both organs, bifurcations occur at a divergence angle of around 100–115°, while rotations of bifurcation events show a dihedral angle of around 60–65°. (B) Mesenchyme as pattern modulator. Separation of mesenchymal and epithelial tissue and subsequent re-arrangement of the mesenchyme around the epithelium destroys any potential mesenchymal pre-patterning. In homotypic recombination experiments, the respective organ-specific branching pattern is maintained, while in heterotypic recombination experiments lung mesenchyme “reprograms” the ureteric bud to adapt a lung-like branching pattern. (C) Regulation of branch point distance in the lung. Fgf10 hypomorphic lungs with a reduction of FGF10 expression by 55% exhibit a wider spacing of the first three lateral branches of the left lung lobe (right lung scheme), while other allelic combinations with a milder reduction in Fgf10 expression do not differ from wild type lungs (left lung scheme). The lung schemes were reproduced from Ramasamy et al. (2007). Accordingly, the ligand-receptor-based Turing mechanism predicts that the spacing of branch tips depends on the rate of ligand expression and is only affected if this rate falls below a certain threshold (dashed line). The graph was reproduced from Celliere et al. (2012). (D) Branch angle remodeling in the kidney. Local bifurcation angles (starting direction of daughter branches) are relatively constant, while global bifurcation angles (direction relative to terminal branch point) show spatial and temporal dynamics. Compressive remodeling of internal branches leads to an increased curvature of these internal branches. Concurrently, terminal branches move closer toward each other which reduces the inter-tip distance d_tip, thereby promoting tip packaging. (E) Branch shape regulation. The shape of branch stalks and tips are regulated differently. The branches in lungs and kidneys show anisotropic growth, meaning that the increase in stalk length l_stalk is larger than in stalk width w_stalk, due to a biased mitosis spindle orientation. Fluid flow and resulting shear stress is able to explain biased elongation in lungs and kidneys. Branch tip shape is regulated by several factors, such as signaling interactions, ECM remodeling or cell tension dynamics, which are highly interconnected. Perturbation of these shape determinants primarily leads to dilated buds characterized by an increased tip circumference c_tip and the absence of cleft formation.