Age-dependent effects of secreted Semaphorins 3A, 3F, and 3E on developinghippocampal axons: In vitro effects and phenotype of Semaphorin 3A (-/-) mice

We studied the role of Semaphorins in the formation of hippocampal connecti ons at embryonic and early postnatal stages. We show that the embryonic ent orhinal cortex has a repulsive effect on embryonic hippocampal axons that d isappears gradually at postnatal stages. Such chemorepulsion is blocked by Neuropilin-1 and -2 blocking antibodies. However, at perinatal stages, the inner layers of the entorhinal cortex attract CA1 axons. At these stages, S ema3A and Sema3F bind commissural and entorhinal axons. Sema3A and Sema3F r epel hippocampal axons at E14-P2, but not at E13. A similar spatiotemporal pattern of chemorepulsion is observed for Sema3A on entorhinal axons, in co ntrast to Sema3F, which repels these axons only at postnatal ages. Sema3E a lso repels hippocampal axons but exclusively at E14. We show that Sema3A an d Sema3F can induce the collapse of hippocampal growth cones and that membr ane-bound Sema3A and Sema3F can guide hippocampal axons in the stripe assay . In sema3A (-/-) mice, the entorhinohippocampal projection is largely norm al although single axons innervate aberrantly the stratum radiatum and the hilus. Thus, the chemorepulsion evoked by Sema3A, Sema3E, and Sema3F is dyn amically regulated in the developing hippocampal formation.