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Age-Dependent Effects of Secreted Semaphorins 3A, 3F, and 3E on Developing Hippocampal Axons: In Vitro Effects and Phenotype of Semaphorin 3A (−/−) Mice

https://doi.org/10.1006/mcne.2001.0999Get rights and content

Abstract

We studied the role of Semaphorins in the formation of hippocampal connections at embryonic and early postnatal stages. We show that the embryonic entorhinal cortex has a repulsive effect on embryonic hippocampal axons that disappears 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, Sema3A and Sema3F bind commissural and entorhinal axons. Sema3A and Sema3F repel hippocampal axons at E14-P2, but not at E13. A similar spatiotemporal pattern of chemorepulsion is observed for Sema3A on entorhinal axons, in contrast to Sema3F, which repels these axons only at postnatal ages. Sema3E also repels hippocampal axons but exclusively at E14. We show that Sema3A and Sema3F can induce the collapse of hippocampal growth cones and that membrane-bound Sema3A and Sema3F can guide hippocampal axons in the stripe assay. In sema3A (−/−) mice, the entorhinohippocampal projection is largely normal although single axons innervate aberrantly the stratum radiatum and the hilus. Thus, the chemorepulsion evoked by Sema3A, Sema3E, and Sema3F is dynamically regulated in the developing hippocampal formation.

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      It is intriguing that two proteases, β- and γ-secretase, so closely involved in the pathogenesis of AD, also appear to coordinately regulate a physiological process of axonal guidance. Although the functional role of Sema3A and CHL1 in the adult brain is not clearly established, it is tempting to speculate that the continued release and expression of these molecules in hippocampus and olfactory bulb, where synaptic plasticity is highly dynamic, is important for modulation and maintenance of brain circuits in adult CNS (Pozas et al., 2001; Sahay et al., 2005). Genetic deficiency of BACE1 and CHL1 affects circuitry in the adult olfactory bulb and/or hippocampus (Cao et al., 2012; Hitt et al., 2012; Rajapaksha et al., 2011), and we find that Sema3A-induced growth cone collapse is also altered in hippocampal neurons treated with BACE1 or γ-secretase inhibitors (Figure S4).

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