Cargando…

PTEN negatively regulates the cell lineage progression from NG2(+) glial progenitor to oligodendrocyte via mTOR-independent signaling

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 p...

Descripción completa

Detalles Bibliográficos
Autores principales: González-Fernández, Estibaliz, Jeong, Hey-Kyeong, Fukaya, Masahiro, Kim, Hyukmin, Khawaja, Rabia R, Srivastava, Isha N, Waisman, Ari, Son, Young-Jin, Kang, Shin H
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839742/
https://www.ncbi.nlm.nih.gov/pubmed/29461205
http://dx.doi.org/10.7554/eLife.32021
_version_ 1783304453044043776
author González-Fernández, Estibaliz
Jeong, Hey-Kyeong
Fukaya, Masahiro
Kim, Hyukmin
Khawaja, Rabia R
Srivastava, Isha N
Waisman, Ari
Son, Young-Jin
Kang, Shin H
author_facet González-Fernández, Estibaliz
Jeong, Hey-Kyeong
Fukaya, Masahiro
Kim, Hyukmin
Khawaja, Rabia R
Srivastava, Isha N
Waisman, Ari
Son, Young-Jin
Kang, Shin H
author_sort González-Fernández, Estibaliz
collection PubMed
description 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 GSK3β, 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 GSK3β activity. OPC-targeted PTEN-GSK3β inactivation may benefit facilitated OL regeneration and myelin repair.
format Online
Article
Text
id pubmed-5839742
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher eLife Sciences Publications, Ltd
record_format MEDLINE/PubMed
spelling pubmed-58397422018-03-09 PTEN negatively regulates the cell lineage progression from NG2(+) glial progenitor to oligodendrocyte via mTOR-independent signaling González-Fernández, Estibaliz Jeong, Hey-Kyeong Fukaya, Masahiro Kim, Hyukmin Khawaja, Rabia R Srivastava, Isha N Waisman, Ari Son, Young-Jin Kang, Shin H eLife Neuroscience 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 GSK3β, 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 GSK3β activity. OPC-targeted PTEN-GSK3β inactivation may benefit facilitated OL regeneration and myelin repair. eLife Sciences Publications, Ltd 2018-02-20 /pmc/articles/PMC5839742/ /pubmed/29461205 http://dx.doi.org/10.7554/eLife.32021 Text en © 2018, González-Fernández et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Neuroscience
González-Fernández, Estibaliz
Jeong, Hey-Kyeong
Fukaya, Masahiro
Kim, Hyukmin
Khawaja, Rabia R
Srivastava, Isha N
Waisman, Ari
Son, Young-Jin
Kang, Shin H
PTEN negatively regulates the cell lineage progression from NG2(+) glial progenitor to oligodendrocyte via mTOR-independent signaling
title PTEN negatively regulates the cell lineage progression from NG2(+) glial progenitor to oligodendrocyte via mTOR-independent signaling
title_full PTEN negatively regulates the cell lineage progression from NG2(+) glial progenitor to oligodendrocyte via mTOR-independent signaling
title_fullStr PTEN negatively regulates the cell lineage progression from NG2(+) glial progenitor to oligodendrocyte via mTOR-independent signaling
title_full_unstemmed PTEN negatively regulates the cell lineage progression from NG2(+) glial progenitor to oligodendrocyte via mTOR-independent signaling
title_short PTEN negatively regulates the cell lineage progression from NG2(+) glial progenitor to oligodendrocyte via mTOR-independent signaling
title_sort pten negatively regulates the cell lineage progression from ng2(+) glial progenitor to oligodendrocyte via mtor-independent signaling
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839742/
https://www.ncbi.nlm.nih.gov/pubmed/29461205
http://dx.doi.org/10.7554/eLife.32021
work_keys_str_mv AT gonzalezfernandezestibaliz ptennegativelyregulatesthecelllineageprogressionfromng2glialprogenitortooligodendrocyteviamtorindependentsignaling
AT jeongheykyeong ptennegativelyregulatesthecelllineageprogressionfromng2glialprogenitortooligodendrocyteviamtorindependentsignaling
AT fukayamasahiro ptennegativelyregulatesthecelllineageprogressionfromng2glialprogenitortooligodendrocyteviamtorindependentsignaling
AT kimhyukmin ptennegativelyregulatesthecelllineageprogressionfromng2glialprogenitortooligodendrocyteviamtorindependentsignaling
AT khawajarabiar ptennegativelyregulatesthecelllineageprogressionfromng2glialprogenitortooligodendrocyteviamtorindependentsignaling
AT srivastavaishan ptennegativelyregulatesthecelllineageprogressionfromng2glialprogenitortooligodendrocyteviamtorindependentsignaling
AT waismanari ptennegativelyregulatesthecelllineageprogressionfromng2glialprogenitortooligodendrocyteviamtorindependentsignaling
AT sonyoungjin ptennegativelyregulatesthecelllineageprogressionfromng2glialprogenitortooligodendrocyteviamtorindependentsignaling
AT kangshinh ptennegativelyregulatesthecelllineageprogressionfromng2glialprogenitortooligodendrocyteviamtorindependentsignaling