Morley, RH; (2012) Investigation into the cellular mechanisms underlying cell sorting by Eph receptors and ephrins. Doctoral thesis , UCL (University College London).

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Abstract

The mechanisms that control the segregation of cells in the developing embryo are essential for normal development. Eph receptors and ephrins are responsible for cell segregation and the maintenance of sharp boundaries between regions of cells, such as those in the adult intestine or the compartments of the developing vertebrate hindbrain. The mechanisms through which they achieve this are not well understood. One widely discussed theory, based on the differential adhesion hypothesis, is that Eph receptors and ephrins influence the relative adhesion between cells in adjacent compartments. The other is that active migratory or repulsive mechanisms are responsible for segregation. Using in vitro assays that were established as part of this project, I have shown that N-cadherin is required for EphB2-ephrinB1 mediated cell sorting, consistent with an important role of cell-cell adhesion in this process. p120 and p0071, which are downstream targets of signalling through EphB2 and have established roles in regulating cadherin stability, are also required for cell segregation by EphB2 and ephrinB1. However, comparison with the segregation of cells expressing different cadherins suggests that differential adhesion is not the main mechanism driving sorting downstream of Eph-ephrins. Instead, I propose that repulsion is the main mechanism driving segregation mediated by EphB2 and ephrinB1 and that N-cadherin is required for general adhesion between all cells, which stabilises the formation of EphB2 cell clusters. Cell behaviour analyses indicate that N-cadherin is not required for the repulsion response of EphB2 cells after interactions with ephrinB1 cells, although it does play a contact-dependent role in cell migration. However, there is a cadherin-independent role of p120 in repulsion downstream of Eph-ephrins, which could contribute to cell sorting. These results support a model where Eph-ephrin mediated repulsion acts in combination with a basal level of cell-cell adhesion to drive cell segregation.

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