Mechanisms Regulating Development and Homeostasis of Mammary Epithelium Organization

Abstract

Many questions remain unanswered about the processes controlling epithelial development and homeostasis in the mammary gland. The monolayer luminal epithelium is generated from multilayered cells within the terminal end bud (TEB), but how this occurs is unknown. Using a modeling approach for a constrained TEB, indicates that most of the cells within the TEB must contribute to the developing ductal monolayer, promoting its elongation and lumen clearance. The predominant theory in the field is that most cells in the interior TEB die to clear the lumen but this seems to only count for a small fraction of luminal clearance. To study this, a modular, quantitative model of intercalation was developed, and it was found that ZO-1 is required for this process. Also shown is the ability for cells to intercalate in a ZO-1-dependent manner after intraductal transplantation. Another open question is how oriented cell division regulates mammary epithelial morphogenesis and homeostasis. Using an approach to specifically perturb mitotic spindle rotation, it was observed that mammary epithelial cells correct their position after misalignment of normal planar cell division – which was previously hypothesized to be a key step in tumor formation. It was found that intercalation (and reintegration) is a pivotal cellular behavior of mammary epithelial cells that supports proper epithelial organization and acts as a defense against dysplasia induced by misoriented division.