Chondroitin Sulfate Acts in Concert with Semaphorin 3A to Guide Tangential Migration of Cortical Interneurons in the Ventral Telencephalon

Abstract

Chondroitin sulfate (CS) carrying proteoglycans (PGs) are widely expressed in the nervous system, and there is increasing evidence that they regulate developmental mechanisms like neurite outgrowth, axonal guidance and neuronal migration. Moreover, they can also act indirectly by organizing and/or modulating growth factors and guidance molecules. We found that chondroitin-4-sulfate is coexpressed with semaphorin 3A (Sema 3A) in the striatal mantle zone (SMZ), a nontarget region of neuropilin (Nrp)-1-expressing cortical interneurons flanking their migratory route in the subpallium. Using in vitro assays, we showed that CS PGs exert a repulsive effect on cortical interneurons, independently of Sema 3A, due to the CS side chains. We further showed that extracellular Sema 3A binds to CS. Disrupting Sema 3A-Nrp-1 signaling led migrating medial ganglionic eminence neurons to inappropriately invade the SMZ and even more so after removal of the CS side chains. Moreover, we found that soluble Sema 3A enhances the CS-induced repulsion in vitro. We concluded that CS acts as a repellent for cortical interneurons and that, in addition, CS restricts secreted Sema 3A within SMZ. Thus, both molecules act in concert to repel cortical interneurons from the SMZ during tangential migration toward the cerebral cortex.

Bidirectional EphrinB3/EphA4 Signaling Mediates the Segregation of Medial Ganglionic Eminence- and Preoptic Area-Derived Interneurons in the Deep and Superficial Migratory Stream

“…1C) and the results of the in vitro assays described above demonstrated that the MGE-derived interneurons enter the deep migratory route. This is consistent with previous studies demonstrating that homotopically transplanted EGFP-explants from the VZ/SVZ of the MGE to the MGE of host slices migrate along the DMS and avoid entering the SMS in the MGE (Zimmer et al, 2008(Zimmer et al, , 2010aRudolph et al, 2010).…”

“…The preferential migration of MGE-derived interneurons along the deep migratory stream is in concordance to what we found with homotopic grafting experiments reported in previous studies (Zimmer et al, 2008(Zimmer et al, , 2010aRudolph et al, 2010), as well as with the migration pattern shown by other groups, with DiIlabeled (Ghanem et al, 2007) or GFP-transfected MGE cells (Flames et al, 2004). EphA4, expressed in the SVZ of the ganglionic eminences, was recently reported to be involved in channeling MGE-derived interneurons into the deep migratory route by repulsive interactions with ephrinA5 and ephrinA3 expressed in the VZ and developing striatum, respectively (Zimmer et al, 2008;Rudolph et al, 2010).…”

“…1 F), a receptor of class III Semaphorins, reported to be expressed by MGE-derived cortical interneurons and to regulate their migration , demarcating the POA and the superficial migratory stream. Thus, in addition to the complementary expression of EphA4 and ephrinB3, the two receptors of class III semaphorins, Nrp-1 and Nrp-2, are also differentially expressed in the deep and superficial migratory route Zimmer et al, 2010a). Using double-labeling experiments in dissociated cells at E14 plus 1 div, we confirmed that Nrp-1 was coexpressed with calbindin in interneurons prepared from the VZ/SVZ of the MGE (the DMS) (Fig.…”

“…Nrp-1 mRNA demarcates the deep route (Zimmer et al, 2010a), while Nrp-2 was detected superficially (Fig. 1 F).…”

Semaphorin 3A Binds to the Perineuronal Nets via Chondroitin Sulfate Type E Motifs in Rodent Brains

“…Its presence affects synapse dynamics (15,17) and may influence plasticity in the mature CNS (22). An interaction between CS and Sema3A has been previously reported in vitro in neuronal cell culture (25) and also by co-localization studies of CSPG and Sema3A during development in vivo (26). More recently, we have shown that Sema3A is concentrated around PNNs in the mature CNS and that it co-localizes with several components of the PNNs (1).…”