Exploring the principles of embryonic mammary gland branching morphogenesis

Abstract

Branching 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. Here we use quantitative 3D morphometrics, time-lapse imaging, manipulation of ex vivo cultured embryonic organs, and mice deficient in the planar cell polarity component Vangl2 to address this question 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 ductal growth-invariant, yet stochastic propensity to branch. The probability to branch was malleable and could be tuned by manipulating the Fgf10 and Tgf-{beta}1 pathways. Finally, our in vivo and ex vivo time-lapse imaging suggested the involvement of tissue rearrangements in mammary branch elongation.