Mechanical control of epithelial lumen formation

Abstract

Epithelial cells differentiate and polarize to build complete epithelial organs during development. The study of epithelial morphogenesis is instrumental to the understanding of disease processes where epithelial polarity is disrupted. Recently, we demonstrated that matrix-induced cell confinement controls the acquisition of three-dimensional epithelial polarity, by modulating the initiation of the apical membrane to form a central lumen (J Cell Biol 2012; 198:1011-1026). Cell confinement can be achieved by use of micropatterned culture chips that allow precise micrometric-scale control of the cell adhesion surface and its composition. Using micropattern chips, we demonstrated that polarizing epithelial cells require high confinement conditions to properly position the centrosome and the trafficking machinery toward the cell-cell contacts and to initiate lumen morphogenesis. Low confinement induces LKB1 and RhoA-mediated cell contractility, which inhibits this mechanism for lumen formation. Deactivation of Myosin-II-mediated contractility rescued normal lumen initiation in low confinement conditions. Our results indicate that a mechanotransduction pathway coordinates nuclear and centrosome positioning to initiate epithelial morphogenesis. Here we discuss the potential candidates that control this process, specifically the polarized activation of Rho and Rab-family GTPases, and also a group of recently characterized nuclear transcription factors.

Keywords: :

• epithelial cell polarity
• MDCK
• lumen formation
• mechanotransduction
• ciliogenesis
• Rho
• Rab

This article refers to:

Acknowledgments

We thank Carmen M. Ruiz-Jarabo for comments on the manuscript and members of the Martin-Belmonte lab for discussions. This work was supported by grants from the Human Frontiers Science Program (HFSP-CDA 00011/2009), MICINN (BFU2011-22622) and CONSOLIDER (CSD2009-00016) to F.M-B. A.E.R-F. is a recipient of a JAE fellowship, from CSIC. An institutional Grant from Fundación Ramón Areces to CBMSO is also acknowledged.