THE EPHA4 AND EPHB1 RECEPTOR TYROSINE KINASES AND EPHRIN-B2 LIGAND REGULATE TARGETED MIGRATION OF BRANCHIAL NEURAL CREST CELLS

Background: During vertebrate head development. neural crest cells mig rate from hindbrain segments to specific branchial arches, where they differentiate into distinct patterns of skeletal structures. The rostr ocaudal identity of branchial neural crest cells appears to be specifi ed prior to migration, so it is important that they are targeted to th e correct destination, In Xenopus embryos, branchial neural crest cell s segregate into four streams that are adjacent during early stages of migration. It is not known what restricts the intermingling of these migrating cell populations and targets them to specific branchial arch es. Here, we investigated the role of Eph receptors and ephrins - medi ators of cell-contact-dependent interactions that have been implicated in neuronal pathfinding - in this targeted migration. Results: Xenopu s EphA4 and EphB1 are expressed in migrating neural crest cells and me soderm of the third arch, and third plus fourth arches, respectively, The ephrin-B2 ligand, which interacts with these receptors, is express ed in the adjacent second arch neural crest and mesoderm. Using trunca ted receptors, we show that the inhibition of EphA4/EphB1 function lea ds to abnormal migration of third arch neural crest cells into second and fourth arch territories. Furthermore, ectopic activation of these receptors by overexpression of ephrin-B2 leads to scattering of third arch neural crest cells into adjacent regions. Similar disruptions occ ur when the expression of ephrin-B2 or truncated receptors is targeted to the neural crest. Conclusions: These data indicate that the comple mentary expression of EphA4/EphB1 receptors and ephrin-B2 is involved in restricting the intermingling of third and second arch neural crest and in targeting third arch neural crest to the correct destination. Together with previous work showing that Eph receptors and ligands med iate neuronal growth cone repulsion, our findings suggest that similar mechanisms are used for neural crest and axon pathfinding.