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GSK3β regulates AKT-induced central nervous system axon regeneration via an eIF2Bε-dependent, mTORC1-independent

Xinzheng Guo1, William D Snider2, Bo Chen1,3

  • 1Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, United States.

Elife
|March 15, 2016
PubMed

Insights

Central nervous system (CNS) axon regeneration is promoted by activating AKT and inhibiting GSK3β. This study identifies eIF2Bε as a key downstream target in the AKT-GSK3β signaling pathway crucial for CNS axon repair.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Regenerative Medicine

Background:

  • Axon regeneration failure is a major challenge following central nervous system (CNS) injury.
  • Modulating the PTEN/mTORC1 pathway in retinal ganglion cells (RGCs) can enhance axon regeneration after optic nerve injury.

Purpose of the Study:

  • To investigate the role of AKT, GSK3β, and eIF2Bε in mediating CNS axon regeneration.
  • To elucidate the signaling cascade involved in promoting axon regrowth and RGC survival after injury.

Main Methods:

  • Investigated the effects of Pten deletion and subsequent AKT activation on RGC axon regeneration.
  • Utilized genetic manipulation (deletion/inactivation/constitutive activation) of GSK3β and eIF2Bε.
  • Assessed axon regeneration and RGC survival in the context of the AKT-GSK3β-eIF2Bε signaling pathway.

Main Results:

  • AKT activation, downstream of Pten deletion, significantly promotes axon regeneration and RGC survival.
  • GSK3β is essential for AKT-mediated axon regeneration; its inhibition promotes regeneration independently of mTORC1.
  • eIF2Bε acts as a novel downstream effector of GSK3β and is critical for both GSK3β and AKT-induced axon regeneration.

Conclusions:

  • The AKT-GSK3β-eIF2Bε signaling module is a key regulator of axon regeneration in the adult mammalian CNS.
  • Targeting this pathway holds therapeutic potential for promoting recovery after CNS injuries.
Keywords:
CNS axon regenerationaxon injurymouseneurosciencesignal transduction

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