RESUMO
Identification of signaling events that contribute to innate spinal cord regeneration in zebrafish can uncover new targets for modulating injury responses of the mammalian central nervous system. Using a chemical screen, we identify JNK signaling as a necessary regulator of glial cell cycling and tissue bridging during spinal cord regeneration in larval zebrafish. With a kinase translocation reporter, we visualize and quantify JNK signaling dynamics at single-cell resolution in glial cell populations in developing larvae and during injury-induced regeneration. Glial JNK signaling is patterned in time and space during development and regeneration, decreasing globally as the tissue matures and increasing in the rostral cord stump upon transection injury. Thus, dynamic and regional regulation of JNK signaling help to direct glial cell behaviors during innate spinal cord regeneration.
Assuntos
Traumatismos da Medula Espinal , Regeneração da Medula Espinal , Animais , Larva , Mamíferos , Regeneração Nervosa/fisiologia , Neuroglia/fisiologia , Medula Espinal , Peixe-Zebra/fisiologia , Proteínas Quinases JNK Ativadas por MitógenoRESUMO
Unlike adult mammals, zebrafish regenerate spinal cord tissue and recover locomotor ability after a paralyzing injury. Here, we find that ependymal cells in zebrafish spinal cords produce the neurogenic factor Hb-egfa upon transection injury. Animals with hb-egfa mutations display defective swim capacity, axon crossing, and tissue bridging after spinal cord transection, associated with disrupted indicators of neuron production. Local recombinant human HB-EGF delivery alters ependymal cell cycling and tissue bridging, enhancing functional regeneration. Epigenetic profiling reveals a tissue regeneration enhancer element (TREE) linked to hb-egfa that directs gene expression in spinal cord injuries. Systemically delivered recombinant AAVs containing this zebrafish TREE target gene expression to crush injuries of neonatal, but not adult, murine spinal cords. Moreover, enhancer-based HB-EGF delivery by AAV administration improves axon densities after crush injury in neonatal cords. Our results identify Hb-egf as a neurogenic factor necessary for innate spinal cord regeneration and suggest strategies to improve spinal cord repair in mammals.
Assuntos
Traumatismos da Medula Espinal , Regeneração da Medula Espinal , Animais , Humanos , Camundongos , Axônios/metabolismo , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/genética , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/metabolismo , Mamíferos , Regeneração Nervosa/genética , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/terapia , Traumatismos da Medula Espinal/metabolismo , Regeneração da Medula Espinal/fisiologia , Peixe-Zebra/genéticaRESUMO
Spinal cord injury is a devastating condition in which massive cell death and disruption of neural circuitry lead to long-term chronic functional impairment and paralysis. In mammals, spinal cord tissue has minimal capacity to regenerate after injury. In stark contrast, the regeneration of a completely transected spinal cord and accompanying reversal of paralysis in adult zebrafish is arguably one of the most spectacular biological phenomena in nature. Here, we review reports from the last decade that dissect the mechanisms of spinal cord regeneration in zebrafish. We highlight recent progress as well as areas requiring emphasis in a line of study that has great potential to uncover strategies for human spinal cord repair.