Chondroitin sulfate acts in concert with semaphorin 3A to guide tangential migration of cortical interneurons in the ventral telencephalon.

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.