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After spinal cord injury, interactions of multiple tissues inhibit neuronal regeneration in mammals, but not in anamniotes, such as zebrafish. These pivotal interactions are poorly understood. Here we analyse the role of the cell signalling moleculesema4abin the cell communication network leading to regenerative neurogenesis after spinal injury in larval zebrafish.Sema4abis expressed by macrophages and gene ablation doubles the rate of regenerative neurogenesis. Disruption of thesema4abreceptorplxnb1a/b, expressed by spinal progenitor cells, also moderately increases regenerative neurogenesis. In addition, single cell transcriptomics reveals altered interactions between macrophages and multiple additional cell types aftersema4abdisruption. Pro-inflammatory cytokines are down-regulated and fibroblasts upregulate expression of the anti-inflammatory cytokinetgfb3.Inhibition oftgfb3abolishes effects ofsema4abdisruption on regenerative neurogenesis. This highlightssema4abas a direct and indirect inhibitor of regenerative neurogenesis and as a potential therapeutic target in non-regenerating mammals.