Progenitor-derived glia are required for spinal cord regeneration in zebrafish

Abstract

Unlike mammals, adult zebrafish undergo spontaneous recovery after major spinal cord injury. Whereas reactive gliosis presents a roadblock for mammalian spinal cord repair, glial cells in zebrafish elicit pro-regenerative bridging functions after injury. Here, we perform genetic lineage tracing, assessment of regulatory sequences, and inducible cell ablation to define mechanisms that direct the molecular and cellular responses of glial cells after spinal cord injury in adult zebrafish. Using a newly generated CreERT2 transgenic line, we show cells that direct expression of the bridging glial marker ctgfa give rise to regenerating glia after injury, with negligible contribution to either neuronal or oligodendrocyte lineages. A 1 kb sequence upstream of the ctgfa gene was sufficient to direct expression in early bridging glia after injury. Finally, ablation of ctgfa-expressing cells using a transgenic nitroreductase strategy impaired glial bridging and recovery of swim behavior after injury. This study identifies key regulatory features, cellular progeny, and requirements of glial cells during innate spinal cord regeneration.

Effect of Voltage-Gated K+Channel Inhibition by 4-aminopyridine in Spinal Cord Injury Recovery in Zebrafish

“…In adults, regenerating axons associate with the elongated glia to cross the site of injury (Goldshmit et al 2012;Mokalled et al 2016). Larval zebrafish also form a glial bridge though the requirement of bridge formation for axon regrowth is still debated (Wehner et al 2017;Zhou et al 2023). We found that larvae treated with 4-AP were more likely to form a glial bridge.…”

“…Unlike mammals which form an inhibitory glial scar, zebrafish form a pro-regenerative glial bridge after SCI (Briona and Dorsky 2014;Goldshmit et al 2012;Klatt Shaw et al 2021;Mokalled et al 2016;Purifoy and Mruk 2024). This bridge is required to permit axons to cross the injury site (Zhou et al 2023). We next determined whether 4-AP affects the glial bridging after SCI (Fig.…”

Retinoic acid, an essential component of the RP organizer, promotes the spatio-temporal segregation of dorsal neural fates

“…These comprised SOX10, SASH1, CALD1, NPR3, MEF2C, LOXL1 , etc. Additionally, it is worth mentioning DLC1 , recently found to mediate cranial NC delamination and migration 44 , and CCN2 , a glial ECM protein with EMT properties 45 . Thus, emergence of the bridge cluster in the treated sample confirms the maintenance of a link between DRG progenitors and melanocytes in absence of RA activity.…”

REDOX Balance in Oligodendrocytes Is Important for Zebrafish Visual System Regeneration

“…In zebrafish, many retinal ganglion cells survive the injury and create new axons that are projected contralaterally towards the OT and vision is restored [10]. Glial cells are very important during regeneration and one key difference between mammals and zebrafish is that, in the former, glia do not form a scar but create a regenerative-permissive environment [1,11,12]. Furthermore, in zebrafish during the degeneration and posterior regeneration of oligodendrocytes, the myelinating cells of the central nervous system (CNS) play a crucial role [5].…”

“…However, the role of these latter oligodendrocytes is more controversial, and they have been described to produce aberrant myelination [14]. The role of the oligodendrocytes during regeneration has been well explored in zebrafish larvae [14] and in the adult spinal cord [12] but their exact role in the visual system remains more obscure.…”