The RSK2-RPS6 axis promotes axonal regeneration in the peripheral and central nervous systems

• Published in: PLoS biology 2023-04, Vol.21 (4), p.e3002044-e3002044
• Main Authors: Decourt, Charlotte, Schaeffer, Julia, Blot, Beatrice, Paccard, Antoine, Excoffier, Blandine, Pende, Mario, Nawabi, Homaira, Belin, Stephane
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Axons - metabolism; Biology and Life Sciences; Cell cycle; Central Nervous System; Circuits; Data recovery; Dorsal root ganglia; Identification and classification; Innervation; Kinases; Life Sciences; Medicine and Health Sciences; Mice; Nerve Regeneration - physiology; Nerves, Peripheral; Nervous system; Neurons; Neurons - physiology; Neuroprotection; Peripheral nervous system; Phosphorylation; Preconditioning; Properties; Protein kinases; Proteins; Rapamycin; Recovery of function; Regeneration; Regeneration (Biology); Research and Analysis Methods; Ribosomal protein S6; Ribosomal protein S6 kinase; Ribosomal Protein S6 Kinases, 90-kDa; Ribosomal proteins; Spinal Cord; Spinal plasticity; Synaptic plasticity; TOR protein
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.3002044

Unlike immature neurons and the ones from the peripheral nervous system (PNS), mature neurons from the central nervous system (CNS) cannot regenerate after injury. In the past 15 years, tremendous progress has been made to identify molecules and pathways necessary for neuroprotection and/or axon regeneration after CNS injury. In most regenerative models, phosphorylated ribosomal protein S6 (p-RPS6) is up-regulated in neurons, which is often associated with an activation of the mTOR (mammalian target of rapamycin) pathway. However, the exact contribution of posttranslational modifications of this ribosomal protein in CNS regeneration remains elusive. In this study, we demonstrate that RPS6 phosphorylation is essential for PNS and CNS regeneration in mice. We show that this phosphorylation is induced during the preconditioning effect in dorsal root ganglion (DRG) neurons and that it is controlled by the p90S6 kinase RSK2. Our results reveal that RSK2 controls the preconditioning effect and that the RSK2-RPS6 axis is key for this process, as well as for PNS regeneration. Finally, we demonstrate that RSK2 promotes CNS regeneration in the dorsal column, spinal cord synaptic plasticity, and target innervation leading to functional recovery. Our data establish the critical role of RPS6 phosphorylation controlled by RSK2 in CNS regeneration and give new insights into the mechanisms related to axon growth and circuit formation after traumatic lesion.