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the “core” regulatory networks, share three common motifs: (i) FGF10 and GDNF are dimers, which likely interact cooperatively with their receptors 25, 26 (Fig. The pathways that are necessary for branching morphogenesis, i.e. Many other signalling pathways modulate the observed branching pattern, but in their absence branching still proceeds. Accordingly, the correct model needs to explain how growth factor signalling becomes concentrated at the points of outgrowth, in spite of uniform ligand production in the adjacent mesenchyme 22, 23, 24. In the absence of signalling, new branches cannot form 1, 2, 15, 16, 17, 18, 19, 20, 21. Thus, FGF10/FGFR2b and GDNF/RET signalling concentrates at the tips of lung and ureteric buds, respectively 10, 11 (Supplementary Figures 1, 2), and induces epithelial outgrowth 12, 13, 14. A deterministic rather than a stochastic process must therefore control branching morphogenesis, and signalling plays a key role 3. The first rounds of lung and kidney branching are stereotyped 8, 9. the distance and angles between new branches, arise remains an open question. The overall subtree organisation in mammary glands and kidneys has been proposed to follow from a density-dependent termination of branching 6, though key assumptions have been challenged 7. The diversity of shapes and functions makes branching morphogenesis an excellent system to establish both general principles of morphogenesis and mechanisms responsible for the shaping of a particular organ 3, 4, 5. Given its flexibility and robustness, we expect that the ligand-receptor-based Turing mechanism constitutes a likely general mechanism to guide branching morphogenesis and other symmetry breaks during organogenesis.īranched epithelial trees are found in many organs, and the capacity of lungs, glands, and kidneys to perform their physiological function depends on the emergence of the correct branching structure 1, 2. We conclude that the ligand-receptor based Turing mechanism presents a common regulatory mechanism for lungs and kidneys, despite the differences in the molecular implementation. We further predict and confirm experimentally that the kidney-specific positive feedback between WNT11 and GDNF permits the dense packing of ureteric tips. We now show that a GDNF-dependent ligand-receptor-based Turing mechanism quantitatively recapitulates branching of cultured wildtype and mutant ureteric buds, and achieves similar branching patterns when directing domain outgrowth in silico. Of all previously proposed signalling-based mechanisms, only a ligand-receptor-based Turing mechanism based on FGF10 and SHH quantitatively recapitulates the lung branching patterns.
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It has remained unclear whether a common regulatory mechanism exists and how organ-specific patterns can emerge. Branching patterns and regulatory networks differ between branched organs.