Mammalian lungs are branched networks containing thousands to millions of airways arrayed in intricate patterns that are crucial for respiration. How such trees are generated during development, and how the developmental patterning information is encoded, have long fascinated biologists and mathematicians. However, models have been limited by a lack of information on the normal sequence and pattern of branching events. Here we present the complete three-dimensional branching pattern and lineage of the mouse bronchial tree, reconstructed from an analysis of hundreds of developmental intermediates. The branching process is remarkably stereotyped and elegant: the tree is generated by three geometrically simple local modes of branching used in three different orders throughout the lung. We propose that each mode of branching is controlled by a genetically encoded subroutine, a series of local patterning and morphogenesis operations, which are themselves controlled by a more global master routine. We show that this hierarchical and modular programme is genetically tractable, and it is ideally suited to encoding and evolving the complex networks of the lung and other branched organs.
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We thank members of the Krasnow laboratory and P. Brown, D. Brutlag, N. Hacohen, D. Kingsley, L. Mündermann, J. Spudich and E. Storm for advice and discussion, and M. Kumar and M. Petersen for help with preparing the figures. This work was funded by grants from National Institutes of Health (to M.A.K. and G.R.M.). M.A.K. is an investigator of the Howard Hughes Medical Institute.
Author Contributions R.J.M. and M.A.K. conceived the experiments. R.J.M. designed and performed experiments and collected data. O.D.K. and G.R.M. contributed to conception and design of the Spry2 experiments and provided genotyped Spry2 embryos. R.J.M. and M.A.K. analysed the data and wrote the manuscript. All authors discussed results and edited the manuscript.
The file contains Supplementary Figure 1, showing the branching lineage of the mouse bronchial tree as 29 separate panels which can be assembled into a single lineage figure.
This file contains Supplementary Figure 1', the aligned and assembled branching lineage of the mouse bronchial tree.
This file contains the Legend to Supplementary Figures 1 and 1'.
This file contains Supplementary Figures 2-5 with Legends.
This file contains additional details of the immunostaining protocols used in this study.
About this article
Scientific Reports (2019)