The hippocampus and septum play central roles in one of the most important spheres of brain function: learning and memory. Although their topographic connections have been known for two decades and topography may be critical for cognitive functions, the basis for hippocamposeptal topographic projection is unknown. We now report for the first time that Elf-1, a membrane-bound eph family ligand, is a candidate molecular tag for the genesis of the hippocamposeptal topographic projection. Elf-i is expressed in an increasing gradient from dorsal to ventral septum. Furthermore, Elf-i selectively allows growth of neurites from topographically appropriate lateral hippocampal neurons, while inhibiting neurite outgrowth by medial hippocampal neurons.Complementary to the expression of Elf-1, an eph family receptor, Bsk, is expressed in the hippocampus in a lateral to medial gradient, consistent with a function as a receptor for Elf-i. Further, Elf-1 specifically bound Bsk, eliciting tyrosine kinase activity. We conclude that the Elf-1/Bsk ligandreceptor pair exhibits traits of a chemoaffinity system for the organization of hippocamposeptal topographic projections.Topographic projection is a general feature of brain architecture, and appears to be critical for appropriate coding and processing of information (1). Nevertheless, little is known about the mechanisms that govern topographic organization. Among the many regions exhibiting topographic relations, the hippocampus and septum have been the focus of intense interest, since these structures play central roles in learning and memory (2-5). The hippocampus projects to the lateral septum and receives afferents from the medial septum (6-8). Moreover, hippocampal projections to the lateral septum are arranged in a precise order. Axons from the medial hippocampus project to the dorsal lateral septum, whereas axons from the lateral hippocampus project to the ventral lateral septum (6-8). Molecular mechanisms underlying these topographic projections are unknown.The development of topographic projections is thought to require both long-range signals to guide axons to the general target area and local cues to specify individual targets precisely for each axon terminal (9-11). Long-range signals are likely to be diffusible, such as netrins, which attract selected, distant growth cones, while repelling others (12)(13)(14)(15). In contrast, local guidance cues must match axon terminals and specific cellular targets, a requirement accommodated by matching fixed tags on afferents and corresponding targets. Complementarity of molecular tags on afferents and targets was first postulated by Sperry in his chemoaffinity hypothesis more than 50 years ago (16,17). Only recently have specific candidate molecules been identified (18)(19)(20)(21)(22). The eph family ligand and receptor, Elf-1 and Mek4, are expressed as complementary gradients in the tectum and retina, respectively (18). The repulsive axon guidance signal, a molecule closely related to Elf-1, repels the growth of retina...