Injured adult neurons regress to an embryonic transcriptional growth state

Nature. 2020 May;581(7806):77-82. doi: 10.1038/s41586-020-2200-5. Epub 2020 Apr 15.

Abstract

Grafts of spinal-cord-derived neural progenitor cells (NPCs) enable the robust regeneration of corticospinal axons and restore forelimb function after spinal cord injury1; however, the molecular mechanisms that underlie this regeneration are unknown. Here we perform translational profiling specifically of corticospinal tract (CST) motor neurons in mice, to identify their 'regenerative transcriptome' after spinal cord injury and NPC grafting. Notably, both injury alone and injury combined with NPC grafts elicit virtually identical early transcriptomic responses in host CST neurons. However, in mice with injury alone this regenerative transcriptome is downregulated after two weeks, whereas in NPC-grafted mice this transcriptome is sustained. The regenerative transcriptome represents a reversion to an embryonic transcriptional state of the CST neuron. The huntingtin gene (Htt) is a central hub in the regeneration transcriptome; deletion of Htt significantly attenuates regeneration, which shows that Htt has a key role in neural plasticity after injury.

MeSH terms

  • Animals
  • Axons / pathology
  • Axons / physiology
  • Cell Proliferation / genetics*
  • Disease Models, Animal
  • Embryo, Mammalian / cytology*
  • Embryo, Mammalian / metabolism*
  • Female
  • Gene Expression Profiling
  • Huntingtin Protein / genetics
  • Mice
  • Nerve Regeneration / genetics*
  • Neural Stem Cells / cytology*
  • Neural Stem Cells / transplantation
  • Neuronal Plasticity
  • Neurons / cytology
  • Neurons / metabolism*
  • Neurons / pathology*
  • Neurons / transplantation
  • Protein Biosynthesis
  • Pyramidal Tracts / cytology
  • Pyramidal Tracts / metabolism
  • Pyramidal Tracts / pathology
  • RNA-Seq
  • Spinal Cord Injuries / genetics
  • Spinal Cord Injuries / pathology
  • Transcription, Genetic*
  • Transcriptome

Substances

  • Htt protein, mouse
  • Huntingtin Protein