Unraveling the principles of mammary gland branching morphogenesis

Abstract

AbstractBranching morphogenesis is a characteristic feature of many essential organs such as the lung, kidney, and most glands, and the net result of two tissue behaviors: branch point initiation and elongation. Each branched organ has a distinct architecture customized to its physiological function, but how patterning occurs in these ramified tubular structures is a fundamental problem of development. The conserved molecular pathways that control branching morphogenesis are well defined, but their contribution to growth versus branch patterning is often challenging to discern. Here we use quantitative 3D morphometrics, time-lapse imaging and manipulation of ex vivo cultured embryonic organs, and genetically modified mice to address these questions in the developing mammary gland. Our results show that the embryonic epithelial trees are highly complex in topology owing to the flexible use of two distinct modes of branch point initiation: lateral branching and tip bifurcation. This non-stereotypy was contrasted by the remarkably constant average branch frequency indicating a time-invariant, yet stochastic propensity to branch. The probability to branch was malleable, and could be increased or decreased by exogenous Fgf10 and Tgf-β1, respectively. Our in vivo and ex vivo time-lapse imaging also suggest involvement of convergent extension in mammary branch elongation, a conclusion supported by the phenotype analysis of mice deficient in the PCP component Vangl2.