Subtype-specific Regeneration of Retinal Ganglion Cells Following Axotomy: Effects of Osteopontin and mTOR Signaling

Neuron. 2015 Mar 18;85(6):1244-56. doi: 10.1016/j.neuron.2015.02.017. Epub 2015 Mar 5.

Abstract

In mammals, few retinal ganglion cells (RGCs) survive following axotomy, and even fewer regenerate axons. This could reflect differential extrinsic influences or the existence of subpopulations that vary in their responses to injury. We tested these alternatives by comparing responses of molecularly distinct subsets of mouse RGCs to axotomy. Survival rates varied dramatically among subtypes, with alpha-RGCs (αRGCs) surviving preferentially. Among survivors, αRGCs accounted for nearly all regeneration following downregulation of PTEN, which activates the mTOR pathway. αRGCs have uniquely high mTOR signaling levels among RGCs and also selectively express osteopontin (OPN) and receptors for the insulin-like growth factor 1 (IGF-1). Administration of OPN plus IGF-1 promotes regeneration as effectively as downregulation of PTEN; however, regeneration is still confined to αRGCs. Our results reveal dramatic subtype-specific differences in the ability of RGCs to survive and regenerate following injury, and they identify promising agents for promoting axonal regeneration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism*
  • Axotomy / methods
  • Cell Survival / physiology
  • Insulin-Like Growth Factor I / metabolism*
  • Mice
  • Nerve Regeneration / physiology*
  • Optic Nerve / physiology
  • Osteopontin / genetics
  • Osteopontin / metabolism*
  • Retinal Ganglion Cells / cytology
  • Retinal Ganglion Cells / metabolism*
  • Signal Transduction* / physiology
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • insulin-like growth factor-1, mouse
  • Osteopontin
  • Insulin-Like Growth Factor I
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse