Zebrafish, in contrast to mammals, regenerate neurons after spinal cord injury, but little is known about the control mechanisms of this process. Here we show that microglia are the main cell type to express the evolutionarily conserved signalling moleculesema4abin the injury site. Deletion ofsema4abdoubles the number of newly generated progenitor cells and neurons after spinal injury. Using scRNAseq of all lesion site cell types after gene disruption, we find thatsema4absupports the microglial activation state and promotes interactions with fibroblasts and neural progenitor cells. Mechanistically,sema4absignals throughplxn1a/breceptors on spinal progenitors and attenuates expression of the neurogenesis-promoting cytokinetgfb3in fibroblasts. Hence, microglia regulate neurogenesis viasema4abin successful spinal cord regeneration in zebrafish, which may be one of the mechanisms preventing regenerative neurogenesis in the mammalian spinal cord.
HIGHLIGHTS
- Microglia control signalling from fibroblasts in a spinal injury site
- Fibroblasts promote regenerative neurogenesis via Tgfb3 signalling
- scRNAseq reveals full complement ofsema4ab-dependent cell type interactions in a spinal injury site
-sema4abstabilises activation state of microglia after injury