September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
AKT Acts as The Nodal Point of PI3K, mTORC1/2 and GSK3β to Promote Optic Nerve Regeneration
Author Affiliations & Notes
  • LINQING MIAO
    Pediatrics, TEMPLE UNIVERSITY, PHILADELPHIA, Pennsylvania, United States
  • Liu Yang
    Pediatrics, TEMPLE UNIVERSITY, PHILADELPHIA, Pennsylvania, United States
  • Haoliang Huang
    Pediatrics, TEMPLE UNIVERSITY, PHILADELPHIA, Pennsylvania, United States
  • Feisi Liang
    Pediatrics, TEMPLE UNIVERSITY, PHILADELPHIA, Pennsylvania, United States
  • Ling Chen
    Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida, United States
  • Yang Hu
    Pediatrics, TEMPLE UNIVERSITY, PHILADELPHIA, Pennsylvania, United States
  • Footnotes
    Commercial Relationships   LINQING MIAO, None; Liu Yang, None; Haoliang Huang, None; Feisi Liang, None; Ling Chen, None; Yang Hu, None
  • Footnotes
    Support  NIH grant EY023295, Shriners Hospitals for Children research grant #85700
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 4386. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to Subscribers Only
      Sign In or Create an Account ×
    • Get Citation

      LINQING MIAO, Liu Yang, Haoliang Huang, Feisi Liang, Ling Chen, Yang Hu; AKT Acts as The Nodal Point of PI3K, mTORC1/2 and GSK3β to Promote Optic Nerve Regeneration. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4386.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract

Purpose : Injuries of optic nerve (ON) in optic neuropathies often result in visual function deficits due to the failure of retinal ganglion cells (RGCs) axons to regenerate. Deletion of phosphatase and tensin homolog (PTEN), the negative regulator of phosphatidylinositol 3-kinase (PI3K), induces RGC axon/ON regeneration, potentially through activation of PI3K. AKT is the major effector of the PI3K pathway; it is phosphorylated by PDK1 and mTOR complex 2 (mTORC2) at two different amino acids. AKT is also the upstream regulator of mTOR complex 1 (mTORC1) and GSK3β. Here we elucidate how AKT coordinates the signaling of these two mTOR complexes and GSK3β in adult mouse RGCs to influence ON regeneration in vivo

Methods : By exploiting the anatomical and technical advantages of adeno-associated virus (AAV)-mediated gene manipulation in RGCs and crushed ON as an in vivo mouse model, we conducted an extensive molecular dissection of the PI3K-PDK1-AKT-mTORC1/GSK3β pathway and the PI3K-mTORC2-AKT pathway specifically in RGCs. 5-7 week old male mice with C57BL/6 background were used in this study.

Results : We found that the predominant AKT isoform in brain and retina, AKT3, induces much more robust axon regeneration than AKT1. We determined definitively by deletion of the key component of mTORC1, RAPTOR, that mTORC1 is necessary for AKT3-induced axon regeneration. We also identified GSK3β as a key molecule for inhibiting axon regeneration, and found that deletion of GSK3β is sufficient to induce axon regeneration. Surprisingly, phosphorylation of T305 and S472 of AKT3 play opposite roles in axon regeneration; mTORC2 inhibits axon regeneration through phosphorylation of AKT3-S472.

Conclusions : Our study revealed a neuron-intrinsic balancing mechanism involving AKT as the nodal point of PI3K, mTORC1/2 and GSK3β signaling, which coordinates both positive and negative cues to regulate adult RGC axon regeneration.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×