Ephrin-dependent growth and pruning of hippocampal axons

Abstract

Neuronal connections are arranged topographically such that the spatial organization of neurons is preserved by their termini in the targets. During the development of topographic projections, axons initially explore areas much wider than the final targets, and mistargeted axons are pruned later. The molecules regulating these processes are not known. We report here that the ligands of the Eph family tyrosine kinase receptors may regulate both the initial outgrowth and the subsequent pruning of axons. In the presence of ephrins, the outgrowth and branching of the receptor-positive hippocampal axons are enhanced. However, these axons are induced later to degenerate. These observations suggest that the ephrins and their receptors may regulate topographic map formation by stimulating axonal arborization and by pruning mistargeted axons.Topographic neuronal projections are regulated, at least in part, by complementary gradients of the Eph family tyrosine kinase receptors and ligands expressed in the pre-and postsynaptic neurons (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). During the development of hippocamposeptal topographic projections, the Eph family receptor EphA5 is expressed in a lateral (low) to medial (high) gradient in the hippocampus (13), whereas three ligands of the receptor, ephrin-A2, A3, and A5, are transcribed in the major subcortical hippocampal target, the lateral septum, in a dorsomedialto-ventrolateral gradient (13,14). In the mature hippocamposeptal topographic map, medial hippocampal neurons, which express high levels of EphA5, project to the ligand-poor dorsomedial target. In contrast, the lateral hippocampal neurons, which express low levels of the Eph receptor, send axons to the ligand-rich ventrolateral target (13-16). The opposing gradients of the receptor and ligand expression suggest that the receptor-ligand interaction contributes to the development of the hippocamposeptal topographic map by negatively regulating axonal growth of receptor-positive medial hippocampal neurons. Similar ligand-receptor gradients also exist in retinotectal system and are proposed to map retinal ganglion axons along the rostrocaudal and dorsoventral axes of the tectum (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(17)(18)(19)(20).In vitro studies using coculture assays in which hippocampal neurons are exposed to the ephrin-expressing cells showed that ephrin-A2 selectively inhibits neurite outgrowth of receptorrich medial hippocampal neurons but has little effects on the growth of the lateral neurites (13). In addition, temporal retina axons, which express high levels of EphA3, a different member of the Eph family, are repelled by ephrin-A2-and A5-containing membrane extracts in stripe assays, in which the extracts with or without the ephrins are laid side by side in narrow stripes (8,9). In contrast, the ephrins have a much weaker repulsive activity against the nasal retina axons, which do not express high levels of the receptor. These in vitro analyses, together with in vivo expression patterns, indica...

The axonal chemorepellant semaphorin 3A is increased in the cerebellum in schizophrenia and may contribute to its synaptic pathology

“…Further support may come from investigation of the neuropilins and plexins, which are semaphorin receptors. 60,61 A relation might also be anticipated between synaptic markers and other gene products involved in axon guidance and pruning, such as ephrins, 62 cadherins, 63 and Otx1. 64 Overall, we assume that sema3A is but one component of a complex set of related gene expression alterations occurring in subjects with schizophrenia across the life span, which together ultimately represent the molecular neuropathology of the disorder.…”

Mistargeting hippocampal axons by expression of a truncated Eph receptor

“…In the adult, ligand proteins detected by EphA5-AP binding appear as a composite gradient of all three ligands (22). We showed previously that these three ligands have similar activity on hippocampal axons (42,50). In addition, in vitro binding studies suggest these ligands have similar biochemical activity (40).…”

“…Evidence that ephrins may have positive effects on axons has been provided by recent studies using cortical and hippocampal neurons (42,43,49). Ephrin-A2, -A3, and -A5 all promoted growth and branching of medial hippocampal axons initially (42). But with prolonged exposure, axon retraction͞fragmentation occurred.…”

“…When R-L Ͼ S, axons have moved beyond the proper target region, and are induced to grow toward the direction of decreasing ligand concentrations to reduce the L value. Evidence that ephrins may have positive effects on axons has been provided by recent studies using cortical and hippocampal neurons (42,43,49). Ephrin-A2, -A3, and -A5 all promoted growth and branching of medial hippocampal axons initially (42).…”

Tiam1 mediates neurite outgrowth induced by ephrin-B1 and EphA2

“…Gao et al have previously shown the two opposing effects of Eph receptors and ephrins on neurite outgrowth in vitro by a series of experiments. Primary cultured rat neurons extended or retracted neurites when they were plated on cells stably expressing various Eph or ephrins on their surface (Gao et al, 1996(Gao et al, , 1998(Gao et al, , 1999(Gao et al, , 2000. However, the molecular basis of such morphological change requires investigation.…”