A unique macrophage subpopulation signals directly to progenitor cells to promote regenerative neurogenesis in the zebrafish spinal cord

Research output: Contribution to journalResearch articleContributedpeer-review


  • Leonardo Cavone - , University of Edinburgh (Author)
  • Tess McCann - , University of Edinburgh (Author)
  • Louisa K. Drake - , University of Edinburgh (Author)
  • Erika A. Aguzzi - , University of Edinburgh (Author)
  • Ana Maria Oprişoreanu - , University of Edinburgh (Author)
  • Elisa Pedersen - , University of Edinburgh (Author)
  • Soe Sandi - , University of Edinburgh (Author)
  • Jathurshan Selvarajah - , University of Edinburgh (Author)
  • Themistoklis M. Tsarouchas - , University of Edinburgh (Author)
  • Daniel Wehner - , University of Edinburgh, Max Planck Institute for the Science of Light, Friedrich-Alexander University Erlangen-Nürnberg (Author)
  • Marcus Keatinge - , University of Edinburgh (Author)
  • Karolina S. Mysiak - , University of Edinburgh (Author)
  • Beth E.P. Henderson - , University of Edinburgh (Author)
  • Ross Dobie - , University of Edinburgh (Author)
  • Neil C. Henderson - , University of Edinburgh (Author)
  • Thomas Becker - , University of Edinburgh (Author)
  • Catherina G. Becker - , University of Edinburgh (Author)


Central nervous system injury re-initiates neurogenesis in anamniotes (amphibians and fishes), but not in mammals. Activation of the innate immune system promotes regenerative neurogenesis, but it is fundamentally unknown whether this is indirect through the activation of known developmental signaling pathways or whether immune cells directly signal to progenitor cells using mechanisms that are unique to regeneration. Using single-cell RNA-seq of progenitor cells and macrophages, as well as cell-type-specific manipulations, we provide evidence for a direct signaling axis from specific lesion-activated macrophages to spinal progenitor cells to promote regenerative neurogenesis in zebrafish. Mechanistically, TNFa from pro-regenerative macrophages induces Tnfrsf1a-mediated AP-1 activity in progenitors to increase regeneration-promoting expression of hdac1 and neurogenesis. This establishes the principle that macrophages directly communicate to spinal progenitor cells via non-developmental signals after injury, providing potential targets for future interventions in the regeneration-deficient spinal cord of mammals.


Original languageEnglish
Pages (from-to)1617-1630.e6
JournalDevelopmental cell
Issue number11
Publication statusPublished - 7 Jun 2021
Externally publishedYes

External IDs

PubMed 34033756



  • AP-1, HDAC1, macrophages, microglia, neural stem cells, regeneration, spinal cord, TNFRSF1