SEMA3A Signaling Controls Layer-Specific Interneuron Branching in the Cerebellum

• Published in: Current biology Vol. 23; no. 10; pp. 850 - 861
• Main Authors: Cioni, Jean-Michel, Telley, Ludovic, Saywell, Véronique, Cadilhac, Christelle, Jourdan, Carole, Huber, Andrea B., Huang, Josh Z., Jahannault-Talignani, Céline, Ango, Fabrice
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 20.05.2013
• Subjects: Animals; Axons; Cerebellum - cytology; Cerebellum - metabolism; Cyclic GMP - metabolism; gamma-Aminobutyric Acid - metabolism; Guanylate Cyclase - metabolism; Interneurons - cytology; Mice; Mice, Knockout; Protein Transport; Semaphorin-3A - metabolism; Signal Transduction
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2013.04.007

GABAergic interneurons regulate the balance and dynamics of neural circuits, in part, by elaborating their strategically placed axon branches that innervate specific cellular and subcellular targets. However, the molecular mechanisms that regulate target-directed GABAergic axon branching are not well understood. Here we show that the secreted axon guidance molecule, SEMA3A, expressed locally by Purkinje cells, regulates cerebellar basket cell axon branching through its cognate receptor Neuropilin-1 (NRP1). SEMA3A was specifically localized and enriched in the Purkinje cell layer (PCL). In sema3A−/− and nrp1sema−/sema− mice lacking SEMA3A-binding domains, basket axon branching in PCL was reduced. We demonstrate that SEMA3A-induced axon branching was dependent on local recruitment of soluble guanylyl cyclase (sGC) to the plasma membrane of basket cells, and sGC subcellular trafficking was regulated by the Src kinase FYN. In fyn-deficient mice, basket axon terminal branching was reduced in PCL, but not in the molecular layer. These results demonstrate a critical role of local SEMA3A signaling in layer-specific axonal branching, which contributes to target innervation. [Display omitted] •Sema3A induced GABAergic axon terminal branching•Local sGC activity is necessary for axon terminal branching•Membrane trafficking of sGC is mediated through protein-protein interaction•FYN induced trafficking of sGC through Y192-specific phosphorylation