A unifying theory of branching morphogenesis

Branching morphogenesis has been a subject of abiding interest. Although much is known about the underlying signaling pathways, it remains unclear how the macroscopic features of branched organs, including their size, network topology and spatial patterning, are encoded. Here we show that, in the mouse mammary gland, kidney and pancreas, these features can be explained quantitatively within a single unifying framework of branching and annihilating random walks. Based on large-scale organ reconstructions, genetic lineage tracing and proliferation kinetics, we show that morphogenesis follows from the collective proliferative activity of sublineage-restricted equipotent self-renewing progenitors localized at ductal tips that drive a process of ductal elongation and stochastic tip bifurcation. By correlating ductal termination with proximity to maturing ducts, this dynamics results in the specification of a complex network of defined density and statistical organization. These results show that branched epithelial structures in mammalian tissues develop as a self-organized process, reliant upon a strikingly simple, but generic, set of local rules, without recourse to a rigid and deterministic sequence of genetically programmed events.