PMID- 28694334
OWN - NLM
STAT- MEDLINE
DCOM- 20170822
LR  - 20190629
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 37
IP  - 31
DP  - 2017 Aug 2
TI  - Loss of Tuberous Sclerosis Complex1 in Adult Oligodendrocyte Progenitor Cells 
      Enhances Axon Remyelination and Increases Myelin Thickness after a Focal 
      Demyelination.
PG  - 7534-7546
LID - 10.1523/JNEUROSCI.3454-16.2017 [doi]
AB  - Although the mammalian target of rapamycin (mTOR) is an essential regulator of 
      developmental oligodendrocyte differentiation and myelination, 
      oligodendrocyte-specific deletion of tuberous sclerosis complex (TSC), a major 
      upstream inhibitor of mTOR, surprisingly also leads to hypomyelination during CNS 
      development. However, the function of TSC has not been studied in the context of 
      remyelination. Here, we used the inducible Cre-lox system to study the function 
      of TSC in the remyelination of a focal, lysolecithin-demyelinated lesion in adult 
      male mice. Using two different mouse models in which Tsc1 is deleted by Cre 
      expression in oligodendrocyte progenitor cells (OPCs) or in premyelinating 
      oligodendrocytes, we reveal that deletion of Tsc1 affects oligodendroglia 
      differently depending on the stage of the oligodendrocyte lineage. Tsc1 deletion 
      from NG2(+) OPCs accelerated remyelination. Conversely, Tsc1 deletion from 
      proteolipid protein (PLP)-positive oligodendrocytes slowed remyelination. 
      Contrary to developmental myelination, there were no changes in OPC or 
      oligodendrocyte numbers in either model. Our findings reveal a complex role for 
      TSC in oligodendrocytes during remyelination in which the timing of Tsc1 deletion 
      is a critical determinant of its effect on remyelination. Moreover, our findings 
      suggest that TSC has different functions in developmental myelination and 
      remyelination.SIGNIFICANCE STATEMENT Myelin loss in demyelinating disorders such 
      as multiple sclerosis results in disability due to loss of axon conductance and 
      axon damage. Encouragingly, the nervous system is capable of spontaneous 
      remyelination, but this regenerative process often fails. Many chronically 
      demyelinated lesions have oligodendrocyte progenitor cells (OPCs) within their 
      borders. It is thus of great interest to elucidate mechanisms by which we might 
      enhance endogenous remyelination. Here, we provide evidence that deletion of Tsc1 
      from OPCs, but not differentiating oligodendrocytes, is beneficial to 
      remyelination. This finding contrasts with the loss of oligodendroglia and 
      hypomyelination seen with Tsc1 or Tsc2 deletion in the oligodendrocyte lineage 
      during CNS development and points to important differences in the regulation of 
      developmental myelination and remyelination.
CI  - Copyright (c) 2017 the authors 0270-6474/17/377534-13$15.00/0.
FAU - McLane, Lauren E
AU  - McLane LE
AUID- ORCID: 0000-0003-2751-7547
AD  - Department of Pharmacology, Physiology, and Neuroscience and Cancer Center, New 
      Jersey Medical School, Rutgers University, Newark, New Jersey 07101, and.
FAU - Bourne, Jennifer N
AU  - Bourne JN
AD  - Department of Cell and Developmental Biology, University of Colorado School of 
      Medicine, Aurora, Colorado 80045.
FAU - Evangelou, Angelina V
AU  - Evangelou AV
AUID- ORCID: 0000-0002-4946-3183
AD  - Department of Pharmacology, Physiology, and Neuroscience and Cancer Center, New 
      Jersey Medical School, Rutgers University, Newark, New Jersey 07101, and.
FAU - Khandker, Luipa
AU  - Khandker L
AD  - Department of Pharmacology, Physiology, and Neuroscience and Cancer Center, New 
      Jersey Medical School, Rutgers University, Newark, New Jersey 07101, and.
FAU - Macklin, Wendy B
AU  - Macklin WB
AUID- ORCID: 0000-0002-1252-0607
AD  - Department of Cell and Developmental Biology, University of Colorado School of 
      Medicine, Aurora, Colorado 80045.
FAU - Wood, Teresa L
AU  - Wood TL
AUID- ORCID: 0000-0002-4480-660X
AD  - Department of Pharmacology, Physiology, and Neuroscience and Cancer Center, New 
      Jersey Medical School, Rutgers University, Newark, New Jersey 07101, and 
      Terri.wood@rutgers.edu.
LA  - eng
GR  - R01 NS082203/NS/NINDS NIH HHS/United States
GR  - R37 NS082203/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20170710
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Tsc1 protein, mouse)
RN  - 0 (Tuberous Sclerosis Complex 1 Protein)
RN  - 0 (Tumor Suppressor Proteins)
SB  - IM
MH  - Animals
MH  - Axons
MH  - Cell Differentiation/physiology
MH  - Cells, Cultured
MH  - Demyelinating Diseases/*metabolism/*pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Myelin Sheath/metabolism/pathology
MH  - Nerve Fibers, Myelinated/metabolism/*pathology
MH  - Nerve Regeneration/physiology
MH  - Oligodendroglia/*metabolism/*pathology
MH  - Stem Cells/*metabolism/pathology
MH  - Tuberous Sclerosis Complex 1 Protein
MH  - Tumor Suppressor Proteins/*metabolism
PMC - PMC5546116
OTO - NOTNLM
OT  - NG2
OT  - TSC
OT  - adult OPCs
OT  - mTOR
OT  - remyelination
EDAT- 2017/07/12 06:00
MHDA- 2017/08/23 06:00
PMCR- 2018/02/02
CRDT- 2017/07/12 06:00
PHST- 2016/11/03 00:00 [received]
PHST- 2017/06/09 00:00 [revised]
PHST- 2017/06/17 00:00 [accepted]
PHST- 2017/07/12 06:00 [pubmed]
PHST- 2017/08/23 06:00 [medline]
PHST- 2017/07/12 06:00 [entrez]
PHST- 2018/02/02 00:00 [pmc-release]
AID - JNEUROSCI.3454-16.2017 [pii]
AID - 3454-16 [pii]
AID - 10.1523/JNEUROSCI.3454-16.2017 [doi]
PST - ppublish
SO  - J Neurosci. 2017 Aug 2;37(31):7534-7546. doi: 10.1523/JNEUROSCI.3454-16.2017. 
      Epub 2017 Jul 10.