The microglia-derived protein Sema4ab attenuates regenerative neurogenesis after spinal cord injury in zebrafish
- 1Center for Regenerative Therapies Dresden at the TU Dresden, Fetscherstr. 105, 01307 Dresden, Germany
Abstract
Zebrafish, in contrast to mammals, regenerate neurons after spinal cord injury, but little is known about the control mechanisms of this process. Here we use scRNA-seq and in vivo experiments to show that sema4ab , mainly expressed by lesion-reactive microglia, attenuates regenerative neurogenesis by changing the complex lesion environment. After spinal injury, disruption of sema4ab doubles the number of newly generated progenitor cells and neurons but attenuates axon regrowth and recovery of swimming function. Disruption of the plxnb1a/b receptors, selectively expressed by neural progenitor cells, increases regenerative neurogenesis. In addition, disruption of sema4ab alters activation state and cytokine expression of microglia, such that fibroblasts increase expression of the cytokine tgfb3 , which strongly promotes regenerative neurogenesis. Hence, sema4ab in microglia attenuates regenerative neurogenesis in multiple ways, likely directly through plxnb1a/b receptors and indirectly, by controlling the inflammatory milieu and tgfb3 levels. Targeting Sema4A-dependent signalling in non-regenerating vertebrates may be a future strategy to improve regenerative outcomes. HIGHLIGHTS - Microglia suppress pro-regenerative fibroblast signalling in a spinal injury site - Fibroblasts promote regenerative neurogenesis via Tgfb3 signalling - sema4ab promotes microglia activation state after spinal injury - scRNA-seq reveals full complement of sema4ab -dependent changes on different cell types during repair of a spinal lesion site
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BibTeX
@article{docamposeara2026microgliaderived,
title = {{The microglia-derived protein Sema4ab attenuates regenerative neurogenesis after spinal cord injury in zebrafish}},
author = {Alberto Docampo-Seara and Mehmet İlyas Coşacak and Kim Heilemann and Friederike Kessel and Ana‐Maria Oprişoreanu and Markus Westphal and Özge Çark and Daniela Zöller and Josi Arnold and Anja Bretschneider and Alisa Hnatiuk and Nikolay Ninov and Catherina G. Becker and Thomas Becker},
journal = {PLoS Biology},
year = {2026},
month = jun,
doi = {10.1371/journal.pbio.3003865},
url = {https://doi.org/10.1371/journal.pbio.3003865},
note = {CC BY},
}
RIS
TY - JOUR
TI - The microglia-derived protein Sema4ab attenuates regenerative neurogenesis after spinal cord injury in zebrafish
AU - Alberto Docampo-Seara
AU - Mehmet İlyas Coşacak
AU - Kim Heilemann
AU - Friederike Kessel
AU - Ana‐Maria Oprişoreanu
AU - Markus Westphal
AU - Özge Çark
AU - Daniela Zöller
AU - Josi Arnold
AU - Anja Bretschneider
AU - Alisa Hnatiuk
AU - Nikolay Ninov
AU - Catherina G. Becker
AU - Thomas Becker
PY - 2026
DA - 2026/06/18
JO - PLoS Biology
DO - 10.1371/journal.pbio.3003865
UR - https://doi.org/10.1371/journal.pbio.3003865
AB - Zebrafish, in contrast to mammals, regenerate neurons after spinal cord injury, but little is known about the control mechanisms of this process. Here we use scRNA-seq and in vivo experiments to show that sema4ab , mainly expressed by lesion-reactive microglia, attenuates regenerative neurogenesis by changing the complex lesion environment. After spinal injury, disruption of sema4ab doubles the number of newly generated progenitor cells and neurons but attenuates axon regrowth and recovery of swimming function. Disruption of the plxnb1a/b receptors, selectively expressed by neural progenitor cells, increases regenerative neurogenesis. In addition, disruption of sema4ab alters activation state and cytokine expression of microglia, such that fibroblasts increase expression of the cytokine tgfb3 , which strongly promotes regenerative neurogenesis. Hence, sema4ab in microglia attenuates regenerative neurogenesis in multiple ways, likely directly through plxnb1a/b receptors and indirectly, by controlling the inflammatory milieu and tgfb3 levels. Targeting Sema4A-dependent signalling in non-regenerating vertebrates may be a future strategy to improve regenerative outcomes. HIGHLIGHTS - Microglia suppress pro-regenerative fibroblast signalling in a spinal injury site - Fibroblasts promote regenerative neurogenesis via Tgfb3 signalling - sema4ab promotes microglia activation state after spinal injury - scRNA-seq reveals full complement of sema4ab -dependent changes on different cell types during repair of a spinal lesion site
SN - 1544-9173
SN - 1545-7885
ER -