Inhibition of Neogenin Promotes Neuronal Survival and Improved Behavior Recovery After Spinal Cord Injury

Neuroscience. 2019 Jun 1;408:430-447. doi: 10.1016/j.neuroscience.2019.03.055. Epub 2019 Mar 31.

Abstract

Following spinal cord trauma, axonal regeneration in the mammalian spinal cord does not occur and functional recovery may be further impeded by retrograde neuronal death. By contrast, lampreys recover after spinal cord injury (SCI) and axons re-connected to their targets in spinal cord. However, the identified reticulospinal (RS) neurons located in the lamprey brain differ in their regenerative capacities - some are good regenerators, and others are bad regenerators - despite the fact that they have analogous projection pathways. Previously, we reported that axonal guidance receptor Neogenin involved in regulation of axonal regeneration after SCI and downregulation of Neogenin synthesis by morpholino oligonucleotides (MO) enhanced the regeneration of RS neurons. Incidentally, the bad regenerating RS neurons often undergo a late retrograde apoptosis after SCI. Here we report that, after SCI, expression of RGMa mRNA was upregulated around the transection site, while its receptor Neogenin continued to be synthesized almost inclusively in the "bad-regenerating" RS neurons. Inhibition of Neogenin by MO prohibited activation of caspases and improved the survival of RS neurons at 10 weeks after SCI. These data provide new evidence in vivo that Neogenin is involved in retrograde neuronal death and failure of axonal regeneration after SCI.

Keywords: Mauthner neuron; Neogenin; RGMa; apoptosis; lamprey; spinal cord regeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / physiopathology
  • Cell Survival / drug effects*
  • Lampreys
  • Membrane Proteins / antagonists & inhibitors*
  • Morpholinos / pharmacology*
  • Neurons / drug effects*
  • Recovery of Function / drug effects*
  • Spinal Cord / drug effects
  • Spinal Cord / physiopathology
  • Spinal Cord Injuries / physiopathology*

Substances

  • Membrane Proteins
  • Morpholinos
  • neogenin