A Unifying Theory of Branching Morphogenesis

The morphogenesis of branched organs remains a subject of abiding interest. Although much is known about the underlying signaling pathways, it remains unclear how macroscopic features of branched organs, including their size, network topology and spatial patterning, are encoded. Here we show that, in mouse mammary gland, kidney and human prostate, these features can be explained quantitatively within a single unifying framework of branching and annihilating random walks. Based on quantitative analyses of large-scale organ reconstructions and proliferation kinetics measurements, we propose that morphogenesis follows from the proliferative activity of equipotent tips that stochastically branch and randomly explore their environment, but compete neutrally for space, becoming proliferatively inactive when in proximity with neighboring ducts. These results show that complex branched epithelial structures in mammalian tissues develop as a self-organized process, reliant upon a strikingly simple, but generic, rule, without recourse to a rigid and deterministic sequence of genetically programmed events.This work was supported by an ERC consolidator grant (648804), research grants from the Dutch Organization of Scientific Research (NWO; 823.02.017), the Dutch Cancer Society (KWF; HUBR 2009-4621), the Association for International Cancer Research (AICR; 13-0297) (all J.v.R), the Wellcome Trust (110326/Z/15/Z to E.H. and 098357/Z/12/Z to B.D.S.), and equipment grants from the Dutch Organization of Scientific Research (NWO; 175.010.2007.00 and 834.11.002). E.H. is funded by a JRF from Trinity College and acknowledges the Bettencourt-Schueller Young Researcher Prize for support. C.L.G.J.S. is funded by a Boehringer Ingelheim Fonds PhD Fellowship. R.S. was supported by the Norman S. Coplon Extramural Grant. R.H. and M.M. were funded by a Cancer Research UK Clinician Scientist Fellowship (Ref C10169/A12173)