Abnormal hippocampal axon bundling in EphB receptor mutant mice.

Axons travel frequently in bundles to reach their target. After arriving at the target, axon terminals defasciculate, migrate to topographically defined positions, and form synapses with appropriate target neurons. Here we present evidence that the B-type receptors of the erythropoietin-producing hepatocellular (Eph) family and a ligand, ephrin-B3, influence hippocampal axon defasciculation. The EphB receptors are expressed in the hippocampus, and the ligand, ephrin-B3, is transcribed in the lateral septum, the major subcortical target of hippocampal neurons. Ephrin-B3 promotes adhesion of hippocampal neurons to the ligand-expressing substrates in vitro, and the loss of the receptor EphB2 abrogates the effects of ephrin-B3. In mice deficient in EphB2 and EphB3, many hippocampal axons remain in bundles. This phenotype was also observed in mice that were specifically deleted for the cytoplasmic domain of EphB2. These observations indicate that the EphB receptors and their ligand regulate hippocampal axon defasciculation at the septal target, possibly through a receptor-mediated forward signaling mechanism.