PTEN negatively regulates the cell lineage progression from NG2+ glial progenitor to oligodendrocyte via mTOR-independent signaling
- Temple University, United States
- Kitasato University School of Medicine, Japan
- Johannes Gutenberg University of Mainz, Germany
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.
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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.
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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PTEN negatively regulates the cell lineage progression from NG2+ glial progenitor to oligodendrocyte via mTOR-independent signaling
eLife 7:e32021.
https://doi.org/10.7554/eLife.32021
