1. Neuroscience
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PTEN negatively regulates the cell lineage progression from NG2+ glial progenitor to oligodendrocyte via mTOR-independent signaling

  1. Estibaliz González-Fernández
  2. Hey-Kyeong Jeong
  3. Masahiro Fukaya
  4. Hyukmin Kim
  5. Rabia R Khawaja
  6. Isha N Srivastava
  7. Ari Waisman
  8. Young-Jin Son
  9. Shin H Kang  Is a corresponding author
  1. Temple University, United States
  2. Kitasato University School of Medicine, Japan
  3. Johannes Gutenberg University of Mainz, Germany
Research Article
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Cite as: eLife 2018;7:e32021 doi: 10.7554/eLife.32021

Abstract

Oligodendrocytes (OLs), the myelin-forming CNS glia, are highly vulnerable to cellular stresses, and a severe myelin loss underlies numerous CNS disorders. Expedited OL regeneration may prevent further axonal damage and facilitate functional CNS repair. Although adult OL progenitors (OPCs) are the primary players for OL regeneration, targetable OPC-specific intracellular signaling mechanisms for facilitated OL regeneration remain elusive. Here, we report that OPC-targeted PTEN inactivation in the mouse, in contrast to OL-specific manipulations, markedly promotes OL differentiation and regeneration in the mature CNS. Unexpectedly, an additional deletion of mTOR did not reverse the enhanced OL development from PTEN-deficient OPCs. Instead, ablation of GSK3b, another downstream signaling molecule that is negatively regulated by PTEN-Akt, enhanced OL development. Our results suggest that PTEN persistently suppresses OL development in an mTOR-independent manner, and at least in part, via controlling GSK3b activity. OPC-targeted PTEN-GSK3b inactivation may benefit facilitated OL regeneration and myelin repair.

Article and author information

Author details

  1. Estibaliz González-Fernández

    Shriners Hospitals Pediatric Research Center, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Hey-Kyeong Jeong

    Shriners Hospitals Pediatric Research Center, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Masahiro Fukaya

    Department of Anatomy, Kitasato University School of Medicine, Sagamihara, Japan
    Competing interests
    The authors declare that no competing interests exist.
  4. Hyukmin Kim

    Shriners Hospitals Pediatric Research Center, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Rabia R Khawaja

    Shriners Hospitals Pediatric Research Center, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Isha N Srivastava

    Shriners Hospitals Pediatric Research Center, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Ari Waisman

    Institute for Molecular Medicine, University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Young-Jin Son

    Shriners Hospitals Pediatric Research Center, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0001-5725-9775
  9. Shin H Kang

    Shriners Hospitals Pediatric Research Center, Temple University, Philadelphia, United States
    For correspondence
    shin.kang@temple.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0002-3692-9802

Funding

National Institute of Neurological Disorders and Stroke (R01NS089586)

  • Shin H Kang

Ellison Medical Foundation (AG-NS-1101-13)

  • Shin H Kang

Shriners Hospitals for Children (85500-PHI-14)

  • Shin H Kang

Shriners Hospitals for Children (84298-PHI)

  • Hey-Kyeong Jeong

National Institute of Neurological Disorders and Stroke (R01NS07693)

  • Young-Jin Son

Shriners Hospitals for Children (86600)

  • Young-Jin Son

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal procedures were conducted in compliance with animal protocols (ACUP 4539 and 4568) approved by Institutional Animal Care and Committee (IACUC) at Temple University School of Medicine.

Reviewing Editor

  1. Beth Stevens, Boston Children's Hospital, Harvard Medical School, United States

Publication history

  1. Received: September 14, 2017
  2. Accepted: February 19, 2018
  3. Accepted Manuscript published: February 20, 2018 (version 1)
  4. Version of Record published: March 6, 2018 (version 2)

Copyright

© 2018, González-Fernández et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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