PMID- 27445141
OWN - NLM
STAT- MEDLINE
DCOM- 20170711
LR  - 20211204
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 36
IP  - 29
DP  - 2016 Jul 20
TI  - Cholesterol Biosynthesis Supports Myelin Gene Expression and Axon Ensheathment 
      through Modulation of P13K/Akt/mTor Signaling.
PG  - 7628-39
LID - 10.1523/JNEUROSCI.0726-16.2016 [doi]
AB  - Myelin, which ensheaths and insulates axons, is a specialized membrane highly 
      enriched with cholesterol. During myelin formation, cholesterol influences 
      membrane fluidity, associates with myelin proteins such as myelin proteolipid 
      protein, and assembles lipid-rich microdomains within membranes. Surprisingly, 
      cholesterol also is required by oligodendrocytes, glial cells that make myelin, 
      to express myelin genes and wrap axons. How cholesterol mediates these distinct 
      features of oligodendrocyte development is not known. One possibility is that 
      cholesterol promotes myelination by facilitating signal transduction within the 
      cell, because lipid-rich microdomains function as assembly points for signaling 
      molecules. Signaling cascades that localize to cholesterol-rich regions of the 
      plasma membrane include the PI3K/Akt pathway, which acts upstream of mechanistic 
      target of rapamycin (mTOR), a major driver of myelination. Through manipulation 
      of cholesterol levels and PI3K/Akt/mTOR signaling in zebrafish, we discovered 
      that mTOR kinase activity in oligodendrocytes requires cholesterol. Drawing on a 
      combination of pharmacological and rescue experiments, we provide evidence that 
      mTOR kinase activity is required for cholesterol-mediated myelin gene expression. 
      On the other hand, cholesterol-dependent axon ensheathment is mediated by Akt 
      signaling, independent of mTOR kinase activity. Our data reveal that 
      cholesterol-dependent myelin gene expression and axon ensheathment are 
      facilitated by distinct signaling cascades downstream of Akt. Because mTOR 
      promotes cholesterol synthesis, our data raise the possibility that cholesterol 
      synthesis and mTOR signaling engage in positive feedback to promote the formation 
      of myelin membrane. SIGNIFICANCE STATEMENT: The speed of electrical impulse 
      movement through axons is increased by myelin, a specialized, cholesterol-rich 
      glial cell membrane that tightly wraps axons. During development, myelin membrane 
      grows dramatically, suggesting a significant demand on mechanisms that produce 
      and assemble myelin components, while it spirally wraps axons. Our studies 
      indicate that cholesterol is necessary for both myelin growth and axon wrapping. 
      Specifically, we found that cholesterol facilitates signaling mediated by the 
      PI3K/Akt/mTOR pathway, a powerful driver of myelination. Because mTOR promotes 
      the expression of genes necessary for cholesterol synthesis, cholesterol 
      formation and PI3K/Akt/mTOR signaling might function as a feedforward mechanism 
      to produce the large amounts of myelin membrane necessary for axon ensheathment.
CI  - Copyright (c) 2016 the authors 0270-6474/16/367628-12$15.00/0.
FAU - Mathews, Emily S
AU  - Mathews ES
AUID- ORCID: 0000-0001-7723-4428
AD  - Department of Pediatrics, University of Colorado School of Medicine, Aurora, 
      Colorado 80045.
FAU - Appel, Bruce
AU  - Appel B
AUID- ORCID: 0000-0003-4500-0672
AD  - Department of Pediatrics, University of Colorado School of Medicine, Aurora, 
      Colorado 80045 bruce.appel@ucdenver.edu.
LA  - eng
GR  - P30 NS048154/NS/NINDS NIH HHS/United States
GR  - R01 NS095679/NS/NINDS NIH HHS/United States
GR  - TL1 TR001081/TR/NCATS NIH HHS/United States
GR  - UL1 TR001082/TR/NCATS NIH HHS/United States
PT  - Journal Article
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Morpholinos)
RN  - 0 (Myelin Proteins)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Zebrafish Proteins)
RN  - 0 (enhanced green fluorescent protein)
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - 97C5T2UQ7J (Cholesterol)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Animals, Genetically Modified
MH  - Axons/*physiology
MH  - Cholesterol/*biosynthesis/pharmacology
MH  - Embryo, Nonmammalian
MH  - Female
MH  - Gene Expression Regulation/genetics/*physiology
MH  - Green Fluorescent Proteins/genetics/metabolism
MH  - Immunosuppressive Agents/pharmacology
MH  - Male
MH  - Morpholinos/pharmacology
MH  - Myelin Proteins/genetics/*metabolism
MH  - Nerve Tissue Proteins/genetics/metabolism
MH  - Oligodendroglia/metabolism
MH  - Phosphatidylinositol 3-Kinases/genetics/*metabolism
MH  - Signal Transduction/genetics/*physiology
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Zebrafish
MH  - Zebrafish Proteins/genetics/metabolism
PMC - PMC4951573
OTO - NOTNLM
OT  - cholesterol
OT  - mTOR
OT  - myelin
OT  - oligodendrocyte
OT  - zebrafish
EDAT- 2016/07/23 06:00
MHDA- 2017/07/14 06:00
PMCR- 2017/01/20
CRDT- 2016/07/23 06:00
PHST- 2016/03/04 00:00 [received]
PHST- 2016/06/06 00:00 [accepted]
PHST- 2016/07/23 06:00 [entrez]
PHST- 2016/07/23 06:00 [pubmed]
PHST- 2017/07/14 06:00 [medline]
PHST- 2017/01/20 00:00 [pmc-release]
AID - 36/29/7628 [pii]
AID - 0726-16 [pii]
AID - 10.1523/JNEUROSCI.0726-16.2016 [doi]
PST - ppublish
SO  - J Neurosci. 2016 Jul 20;36(29):7628-39. doi: 10.1523/JNEUROSCI.0726-16.2016.