The tracheal system of Drosophila melanogaster is one of the best characterized multicellular branched organs. Branchless (BNL), a fibroblast growth factor (FGF) ligand, initiates the branching process by triggering cell migration, and functions at the top of a hierarchy of processes that orchestrate branching (for example, branch initiation, branch extension, cell competition, cell intercalation and cell determination).
Recent studies have unravelled unexpected similarities in cellular behaviour between tracheal branching in D. melanogaster and angiogenic sprouting in vertebrates. Vascular endothelial growth factor A (VEGFA), encoded by one of the four Vegf genes in mammals, is key to most of the morphogenetic events during angiogenesis that control migration, proliferation and survival of endothelial cells.
Tracheal system and vasculature development are conceptually different from lung and kidney development. The lung and kidney occupy a defined volume in an organism and the branching process is essentially limited to a 'bag' of mesenchymal tissue. Lung and kidney branching is controlled by various reciprocal feedback interactions between the branching epithelium and the surrounding mesenchyme. FGF and glial cell-derived neurotrophic factor (GDNF) in lung and kidney, respectively, are specifically expressed by the stroma in regions that prefigure branch outgrowth.
Mammary epithelial branching is also regulated by various signals expressed by the epithelium or the stroma, including bone morphogenetic protein (BMP), Wnt and epidermal growth factor (EGF) proteins. Moreover, hormonal control has an important role in mammary gland branching. However, in sharp contrast to the other branching processes, no signal has been identified that is specifically expressed by the stroma in regions that prefigure branch outgrowth. The mammary gland branching process therefore seems to be stochastic.
Growing branches are polarized through the establishment of a tip and a stalk. In the fly tracheal system and the vertebrate vasculature, a few cells or a single cell take up the lead position and are followed by stalk cells. Epithelial cells compete for leading positions. The cell interactions that determine the tip and stalk structures depend on Notch-dependent lateral inhibition at the single cell level.
In lung, kidney and mammary gland development, the cellular complexity is much higher than in the fly trachea and vertebrate vasculature as the branching tip is composed of many cells, which makes it unlikely that the Notch pathway is involved in the segregation of tip and stalk cells. Cell proliferation is a major factor contributing to elongation and branching in these complex systems.
Branched structures are evident at all levels of organization in living organisms. Many organs, such as the vascular system, lung, kidney and mammary gland, are heavily branched. In each of these cases, equally fascinating questions have been put forward, including those that address the cellular and molecular mechanisms that regulate the branching process itself, such as where the branches are initiated and how they extend and grow in the right direction. Recent experiments suggest that cell competition and cell rearrangements might be conserved key features in branch formation and might be controlled by local cell signalling.
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We thank H. Gerhardt, R. Metzger, Z. Werb, F. Costantini, C. Kuehlemeier and R. Smith for stimulating discussions. We apologize for not being able to cite all relevant primary publications because of space restrictions.
- Endothelial tissue
A tissue made up of flattened endothelial cells that forms the interior surface of blood vessels.
The major Ca2+-dependent cell–cell adhesion molecule involved in the establishment of embryonic epithelium and in ensuring that epithelial cells remain bound together.
The epithelium that covers the body surface of the early embryo.
- Actin–myosin filaments
The parallel arrangement of actin and myosin filaments. Using the hydrolysis of ATP, myosin can make the two types of filament slide on each other to shorten the structure as a whole.
- Tracheal sac
A cluster of about 80 ectodermal cells that have invaginated within the embryo and formed an epithelial sac.
A thin, dynamic cytoplasmic projection covered with cell membrane that extends from the leading edge of migrating cells. Filopodia contain actin filament bundles and are presumably involved in exploring the cell environment.
The process during which cells insert between cells that are already in contact with each other.
A molecule with a chemotaxis-inducing effect on motile cells, which migrate towards its source.
The lack of an adequate oxygen supply to an area of the body.
- Angiogenic sprouting
The growth of new blood vessels from pre-existing vessels.
A star-shaped cell that provides support and protection for neurons in the central nervous system.
- Intersegmental vessel
A vessel that carries blood from the dorsal aorta between somites to the dorsal side of the neural tube.
- Axonal growth cone
The motile extension of a developing axon. Axonal growth cones use external cues to guide their movements.
- Apical ectodermal ridge
The thickening of the ectoderm rim at the tip of a developing limb bud in a vertebrate embryo.
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Affolter, M., Zeller, R. & Caussinus, E. Tissue remodelling through branching morphogenesis. Nat Rev Mol Cell Biol 10, 831–842 (2009). https://doi.org/10.1038/nrm2797
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