In vivo cell sorting in complementary segmental domains mediated by Eph receptors and ephrins

The restriction of intermingling between specific cell populations is crucial for the maintenance of organized patterns during development. A striking example is the restriction of cell mixing between segments in the insect epidermis1 and the vertebrate hindbrain2 that may enable each segment to maintain a distinctidentity. In the hindbrain, this is a result of different adhesive properties of odd- and even-numbered segments (rhombomeres)3,4, but an adhesion molecule with alternating segmental expression has not been found. However, blocking experiments suggest that Eph-receptor tyrosine kinases may be required for the segmental restriction of cells5. Eph receptors and their membrane-bound ligands, ephrins, are expressed in complementary rhombomeres6 and, by analogy with their roles in axon pathfinding7,8, could mediate cell repulsion at boundaries. Remarkably, transmembrane ephrins can themselves transduce signals9,10, raising the possibility that bi-directional signalling occurs between adjacent ephrin- and Eph-receptor-expressing cells. We report here that mosaic activation of Eph receptors leads to sorting of cells to boundaries in odd-numbered rhombomeres, whereas mosaic activation of ephrins results in sorting to boundaries in even-numbered rhombomeres. These data implicate Eph receptors and ephrins in the segmental restriction of cell intermingling.