Single-cell analysis of innate spinal cord regeneration identifies intersecting modes of neuronal repair

• Published in: Nature communications Vol. 15; no. 1; pp. 6808 - 21
• Main Authors: Saraswathy, Vishnu Muraleedharan, Zhou, Lili, Mokalled, Mayssa H.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.08.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 14/1; 14/19; 14/32; 38/62; 38/91; 42/41; 49/39; 631/378/1687/1825; 631/378/340; 631/378/87; 64/116; Animals; Animals, Genetically Modified; CRISPR; CRISPR-Cas Systems; Danio rerio; Disease Models, Animal; Functional plasticity; GABAergic Neurons - metabolism; Gene expression; Gene sequencing; Glutamatergic transmission; Humanities and Social Sciences; Injury analysis; multidisciplinary; Mutagenesis; Nerve Regeneration - physiology; Neurogenesis; Neurogenesis - genetics; Neuronal Plasticity - physiology; Neurons; Neurons - metabolism; Neurons - physiology; Neuroplasticity; Recovery of Function; Regeneration; Science; Science (multidisciplinary); Single-Cell Analysis; Spinal Cord - metabolism; Spinal cord injuries; Spinal Cord Injuries - metabolism; Spinal Cord Regeneration; Spinal plasticity; Zebrafish; γ-Aminobutyric acid
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-50628-y

Adult zebrafish have an innate ability to recover from severe spinal cord injury. Here, we report a comprehensive single nuclear RNA sequencing atlas that spans 6 weeks of regeneration. We identify cooperative roles for adult neurogenesis and neuronal plasticity during spinal cord repair. Neurogenesis of glutamatergic and GABAergic neurons restores the excitatory/inhibitory balance after injury. In addition, a transient population of injury-responsive neurons (iNeurons) show elevated plasticity 1 week post-injury. We found iNeurons are injury-surviving neurons that acquire a neuroblast-like gene expression signature after injury. CRISPR/Cas9 mutagenesis showed iNeurons are required for functional recovery and employ vesicular trafficking as an essential mechanism that underlies neuronal plasticity. This study provides a comprehensive resource of the cells and mechanisms that direct spinal cord regeneration and establishes zebrafish as a model of plasticity-driven neural repair. The roadmap to promote neural repair after spinal cord injury remains elusive. Here, longitudinal single-cell sequencing in adult zebrafish identifies intersecting modes of neuronal plasticity and neurogenesis during innate neural repair.