PMID- 35235799
OWN - NLM
STAT- MEDLINE
DCOM- 20220411
LR  - 20220503
IS  - 2211-1247 (Electronic)
VI  - 38
IP  - 9
DP  - 2022 Mar 1
TI  - Cholesterol biosynthesis defines oligodendrocyte precursor heterogeneity between 
      brain and spinal cord.
PG  - 110423
LID - S2211-1247(22)00147-4 [pii]
LID - 10.1016/j.celrep.2022.110423 [doi]
AB  - Brain and spinal cord oligodendroglia have distinct functional characteristics, 
      and cell-autonomous loss of individual genes can result in different regional 
      phenotypes. However, a molecular basis for these distinctions is unknown. Using 
      single-cell analysis of oligodendroglia during developmental myelination, we 
      demonstrate that brain and spinal cord precursors are transcriptionally distinct, 
      defined predominantly by cholesterol biosynthesis. We further identify the 
      mechanistic target of rapamycin (mTOR) as a major regulator promoting cholesterol 
      biosynthesis in oligodendroglia. Oligodendroglia-specific loss of mTOR decreases 
      cholesterol biosynthesis in both the brain and the spinal cord, but mTOR loss in 
      spinal cord oligodendroglia has a greater impact on cholesterol biosynthesis, 
      consistent with more pronounced deficits in developmental myelination. In the 
      brain, mTOR loss results in a later adult myelin deficit, including 
      oligodendrocyte death, spontaneous demyelination, and impaired axonal function, 
      demonstrating that mTOR is required for myelin maintenance in the adult brain.
CI  - Copyright (c) 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
FAU - Khandker, Luipa
AU  - Khandker L
AD  - Department of Pharmacology, Physiology & Neuroscience, New Jersey Medical School, 
      Rutgers University, Newark, NJ 07103, USA.
FAU - Jeffries, Marisa A
AU  - Jeffries MA
AD  - Department of Pharmacology, Physiology & Neuroscience, New Jersey Medical School, 
      Rutgers University, Newark, NJ 07103, USA.
FAU - Chang, Yun-Juan
AU  - Chang YJ
AD  - Office of Advance Research Computing, Rutgers University, Piscataway, NJ 08854, 
      USA.
FAU - Mather, Marie L
AU  - Mather ML
AD  - Department of Pharmacology, Physiology & Neuroscience, New Jersey Medical School, 
      Rutgers University, Newark, NJ 07103, USA.
FAU - Evangelou, Angelina V
AU  - Evangelou AV
AD  - Department of Pharmacology, Physiology & Neuroscience, New Jersey Medical School, 
      Rutgers University, Newark, NJ 07103, USA.
FAU - Bourne, Jennifer N
AU  - Bourne JN
AD  - Department of Cell and Developmental Biology, University of Colorado School of 
      Medicine, Aurora, CO 80045, USA.
FAU - Tafreshi, Azadeh K
AU  - Tafreshi AK
AD  - Department of Psychiatry, New Jersey Medical School, Rutgers University, Newark, 
      NJ 07103, USA.
FAU - Ornelas, Isis M
AU  - Ornelas IM
AD  - Department of Pharmacology, Physiology & Neuroscience, New Jersey Medical School, 
      Rutgers University, Newark, NJ 07103, USA.
FAU - Bozdagi-Gunal, Ozlem
AU  - Bozdagi-Gunal O
AD  - Department of Psychiatry, New Jersey Medical School, Rutgers University, Newark, 
      NJ 07103, USA.
FAU - Macklin, Wendy B
AU  - Macklin WB
AD  - Department of Cell and Developmental Biology, University of Colorado School of 
      Medicine, Aurora, CO 80045, USA.
FAU - Wood, Teresa L
AU  - Wood TL
AD  - Department of Pharmacology, Physiology & Neuroscience, New Jersey Medical School, 
      Rutgers University, Newark, NJ 07103, USA. Electronic address: 
      terri.wood@rutgers.edu.
LA  - eng
GR  - F31 NS108521/NS/NINDS NIH HHS/United States
GR  - R01 NS082203/NS/NINDS NIH HHS/United States
GR  - R37 NS082203/NS/NINDS NIH HHS/United States
GR  - S10 OD018206/OD/NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cell Rep
JT  - Cell reports
JID - 101573691
RN  - 97C5T2UQ7J (Cholesterol)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Brain/metabolism
MH  - Cell Differentiation/genetics
MH  - Cholesterol
MH  - Myelin Sheath/metabolism
MH  - *Oligodendrocyte Precursor Cells/metabolism
MH  - Oligodendroglia/metabolism
MH  - Spinal Cord/metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC8988216
MID - NIHMS1785215
OTO - NOTNLM
OT  - cholesterol
OT  - mTOR
OT  - myelin
OT  - myelin maintenance
OT  - myelination
OT  - oligodendrocyte
OT  - oligodendrocyte heterogeneity
OT  - oligodendrocyte precursor
OT  - single-cell sequencing
COIS- Declaration of interests The authors declare no competing interests.
EDAT- 2022/03/03 06:00
MHDA- 2022/04/12 06:00
PMCR- 2022/04/07
CRDT- 2022/03/02 20:06
PHST- 2021/03/12 00:00 [received]
PHST- 2022/01/04 00:00 [revised]
PHST- 2022/02/02 00:00 [accepted]
PHST- 2022/03/02 20:06 [entrez]
PHST- 2022/03/03 06:00 [pubmed]
PHST- 2022/04/12 06:00 [medline]
PHST- 2022/04/07 00:00 [pmc-release]
AID - S2211-1247(22)00147-4 [pii]
AID - 10.1016/j.celrep.2022.110423 [doi]
PST - ppublish
SO  - Cell Rep. 2022 Mar 1;38(9):110423. doi: 10.1016/j.celrep.2022.110423.