Pdgfrβ signaling orchestrates meningeal repair via the mobilization of arachnoid cells.

Abstract Zebrafish possess remarkable regeneration abilities, including the capacity to repair their central nervous system (CNS). Leveraging the optical accessibility of the zebrafish brain, we investigated the mechanisms underlying meningeal repair following laser-induced brain injuries to the optic tectum. In previous work, using live imaging of laser-induced surface injuries to the optic tectum in juvenile zebrafish, we identified a population of flat PDGFRβ+ cells that rapidly migrate to the wound site and contribute to meningeal repair. Here, using pharmacological inhibition or genetic perturbation of PDGFRβ, we show that recruitment of these PDGFRβ+ meningeal cells is strongly dependent on PDGFRβ signaling, unlike recruitment of PDGFRβ+ pericytes deeper in the wound. Furthermore, PDGFRβ inhibition diminishes neurite regrowth and macrophage recruitment. Using photoconversion assays, we traced the origin of PDGFRβ+ meningeal cells that migrated to the wound in response to injury, in the midbrain-forebrain and midbrain-hindbrain sulci. Our findings highlight PDGFRβ’s pivotal role in orchestrating meningeal repair and reveal novel cellular dynamics during CNS regeneration. These results provide insights into potential therapeutic strategies for enhancing brain repair and mitigating fibrosis in mammals, where meningeal scarring remains a barrier to CNS regeneration. Highlights PDGFRβ signaling orchestrates the rapid accumulation of meningeal cells at CNS injury sites to drive tissue remodeling. PDGFR activity acts as a critical regulator, co-recruiting PDGFRβ+ meningeal cells and mfap4+ macrophages to the lesion. Meningeal cells are essential for neural repair, with PDGFR inhibition leading to significantly reduced neurite density. Zebrafish maintain locomotor resilience post-injury, identifying a clear distinction between meningeal-driven axonal regrowth and basic motor circuitry recovery. Establishes a high-resolution zebrafish platform to identify conserved meningeal targets for mammalian CNS regeneration. Competing Interest Statement The authors have declared no competing interest.