Mechanical control of epithelial cell division

Abstract

Epithelia form essential barriers that protect tissues from the external environment, yet at the same time display high rates of cellular turnover. To ensure the integrity of this barrier while preventing overgrowth, epithelial cell divisions must be tightly balanced with cell loss. Moreover, cells undergo complex morphological changes as they divide, during which barrier integrity must be maintained. In this thesis, we describe how both of these processes rely on mechanical forces that cells exert on each other and the cellular response to these forces. We demonstrate that the rate of epithelial cell division is controlled by cell density, which cells sense through coinciding changes in intercellular forces exerted on E-cadherin adhesions. E-cadherin transduces these forces to regulate Cdk1, the gatekeeper kinase of mitotic entry, thereby controlling the length of G2-phase and timing of mitotic entry. We provide evidence that in turn, Cdk1 also controls the organization cell-cell adhesions, revealing a dynamic interplay between cell-cell adhesion and the cell cycle. Finally, we uncover that as cells enter mitosis and round up they also exert tensile forces on their neighbors. These forces lead to changes in the composition of the E-cadherin adhesion that occur selectively at one side of the cell-cell contact. This asymmetric response is essential to maintain epithelial barrier integrity while at the same time enable the shape changes of the mitotic cell. Altogether, these findings underscore that force-sensitive E-cadherin adhesions fulfil a central role in the regulation of cell division in a multicellular context.