Branching morphogenesis governs the formation of many organs such as lung, kidney, and the neurovascular system. Many studies have explored system-specific molecular and cellular regulatory mechanisms, as well as self-organizing rules underlying branching morphogenesis. However, in addition to local cues, branched tissue growth can also be influenced by global guidance. Here, we develop a theoretical framework for a stochastic self-organized branching process in the presence of external cues. Combining analytical theory with numerical simulations, we predict differential signatures of global vs. local regulatory mechanisms on the branching pattern, such as angle distributions, domain size, and space-filling efficiency. We find that branch alignment follows a generic scaling law determined by the strength of global guidance, while local interactions influence the tissue density but not its overall territory. Finally, using zebrafish innervation as a model system, we test these key features of the model experimentally. Our work thus provides quantitative predictions to disentangle the role of different types of cues in shaping branched structures across scales.
We thank all members of our respective groups for helpful discussion on the paper. The authors are also grateful to Prof. Abdel El. Manira for support and sharing Tg(HUC:Gal4;UAS:Synaptohysin-GFP), to Haohao Wu for discussion, and thank Elena Zabalueva for the zebrafish schematic. The authors also acknowledge Zebrafish core facility, Genome Engineering Zebrafish and Biomedicum Imaging Core from the Karolinska Institutet for technical support. This work received funding from the ERC under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 851288 to E.H.) and under the Marie Skłodowska-Curie grant agreement No. 754411 (to M.C.U.); Swedish Research Council (to F.L., I.A. and S.H.); Knut and Alice Wallenberg Foundation (F.L. and I.A.); Swedish Brain Foundation (F.L. and S.H.); Ming Wai Lau Foundation (to F.L.); StratRegen (to F.L.); ERC Consolidator grant STEMMING-FROM-NERVE and ERC Synergy Grant KILL-OR-DIFFERENTIATE (to I.A.); Bertil Hallsten Research Foundation (to I.A.); Cancerfonden (to I.A.); the Paradifference Foundation (to I.A.); Austrian Science Fund (to I.A.); and StratNeuro (to S.H.).
Ucar MC, Kamenev D, Sunadome K, et al. Theory of branching morphogenesis by local interactions and global guidance. Nature Communications. 2021;12(1). doi:10.1038/s41467-021-27135-5
Ucar, M. C., Kamenev, D., Sunadome, K., Fachet, D. C., Lallemend, F., Adameyko, I., … Hannezo, E. B. (2021). Theory of branching morphogenesis by local interactions and global guidance. Nature Communications. Springer Nature. https://doi.org/10.1038/s41467-021-27135-5
Ucar, Mehmet C, Dmitrii Kamenev, Kazunori Sunadome, Dominik C Fachet, Francois Lallemend, Igor Adameyko, Saida Hadjab, and Edouard B Hannezo. “Theory of Branching Morphogenesis by Local Interactions and Global Guidance.” Nature Communications. Springer Nature, 2021. https://doi.org/10.1038/s41467-021-27135-5.
M. C. Ucar et al., “Theory of branching morphogenesis by local interactions and global guidance,” Nature Communications, vol. 12, no. 1. Springer Nature, 2021.
Ucar MC, Kamenev D, Sunadome K, Fachet DC, Lallemend F, Adameyko I, Hadjab S, Hannezo EB. 2021. Theory of branching morphogenesis by local interactions and global guidance. Nature Communications. 12(1), 6830.
Ucar, Mehmet C., et al. “Theory of Branching Morphogenesis by Local Interactions and Global Guidance.” Nature Communications, vol. 12, no. 1, 6830, Springer Nature, 2021, doi:10.1038/s41467-021-27135-5.
All files available under the following license(s):
Creative Commons Attribution 4.0 International Public License (CC-BY 4.0):
2021_NatComm_Ucar.pdf 2.30 MB
Link(s) to Main File(s)