| dc.description.abstract | Transporting epithelia of the kidney and small intestine utilize actin-supported cell surface protrusions, known as microvilli, to expand surface area available for solute transport. Microvilli found on the surface of these epithelia constitute a well-organized “brush border” made up of thousands of protrusions connected via a tip-localized intermicrovillar adhesion complex (IMAC) composed of cadherins CDHR2 and CDHR5. Experiments in this dissertation project revealed that at time points early in differentiation, epithelial cells present two general populations of microvilli: (1) a marginal population at the edges of cells, characterized by high protrusion density, and (2) a medial population characterized by much lower protrusion density. Strikingly, marginal microvilli extend across cell-cell junctions to physically contact microvilli on neighboring cells, using “transjunctional” IMACs. Additionally, transjunctional IMACs are more stable than those bridging medial clusters of microvilli and serve as an anchoring point for nascent microvilli at cell margins. Given the stabilizing nature of transjunctional IMACs, basolateral junctions may be influenced by apical CDHR2/CDHR5 transjunctional contacts. Indeed, in a CDHR2 KO mouse model and in CDHR2 KO CL4 and CACO-2BBE cells, endogenous signal of tight and adherens junction proteins and non-muscle myosin 2-c are reduced. As a result, CDHR2 KO cells exhibit abnormal cell morphologies, increased junction permeability, and impaired collective cell migration. Overall, these findings suggest a new, adhesion-based mechanism for the stabilization of microvilli and support of cell junctions, changing the established understanding of how transporting epithelial cells utilize cell-cell contacts to create optimal tissue structure. | |
