Demarque, M. | bioRxiv Science

bioRxiv2026

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

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 PDGFR{beta}+ cells that rapidly migrate to the wound site and contribute to meningeal repair. Here, using pharmacological inhibition or genetic perturbation of PDGFR{beta}, we show that recruitment of these PDGFR{beta}+ meningeal cells is strongly dependent on PDGFR{beta} signaling, unlike recruitment of PDGFR{beta}+ pericytes deeper in the wound. Furthermore, PDGFR{beta} inhibition diminishes neurite regrowth and macrophage recruitment. Using photoconversion assays, we traced the origin of PDGFR{beta}+ meningeal cells that migrated to the wound in response to injury, in the midbrain-forebrain and midbrain-hindbrain sulci. Our findings highlight PDGFR{beta}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. HighlightsPDGFR{beta} 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 PDGFR{beta}+ 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.

cell biology↗

bioRxiv2021

Plasticity of the dopaminergic phenotype and of locomotion in larval zebrafish induced by changes in brain excitability during the embryonic period.

During the embryonic period, neuronal communication starts before the establishment of the synapses with alternative forms of neuronal excitability, called here Embryonic Neuronal Excitability (ENE). ENE has been shown to modulate the unfolding of development transcriptional programs but the global consequences for the developing organisms are not all understood. Here we monitored calcium transients in zebrafish embryos as a proxy for ENE to assess the efficacy of transient pharmacological treatments to either increase or decrease ENE. Increasing or decreasing ENE for 24 hours at 2 days post fertilization (dpf), at the end of the embryonic period, promoted respectively an increase or a decrease in the numbers of dopamine (DA) neurons in the telencephalon and in the olfactory bulb of zebrafish larvae at 6 dpf. This plasticity of dopaminergic specification occurs within a stable population of vMAT2-positive cells, hence identifying an unanticipated biological marker for this reserve pool of of DA neurons that can be recruited by increasing ENE. Modulating ENE also affected larval locomotion several days after the end of the treatments. In particular, the increase of ENE from 2 to 3 dpf promoted hyperlocomotion of larvae at 6 dpf, reminiscent of endophenotypes reported for Attention Deficit with Hyperactivity Disorders and schizophrenia in zebrafish. These results provide a convenient framework to identify environmental factors that could disturb ENE as well as to study the molecular mechanisms linking ENE to neurotransmitter specification, with relevance to the pathogenesis of neurodevelopmental disorders. Significance Statement- Spontaneous calcium transients, used as a proxy for Embryonic Neuronal Excitability (ENE), are detected in the forebrain of embryonic zebrafish. - Short-term pharmacological treatments by bath application could increase or decrease ENE. - The post-mitotic differentiation of the dopaminergic phenotype is modulated by ENE in the zebrafish forebrain. - The plasticity of the dopaminergic specification occurs within a reserve pool of vMAT2-positive cells. - Transient increase of ENE at the end of the embryonic period induces hyperlocomotion, a phenotype associated with ADHD and schizophrenia in this model. - Our results open clinically relevant perspectives to study the pathogenesis of neurodevelopmental disorders in zebrafish.

neuroscience↗