Myelination

Aman Kumar Naik
Integrated M.Sc.
9/11/2015 :: National Institute of Science Education and Research ::
Myelination

DOI: 10.1126/science.1190927
, 779 (2010);330Science
Ben Emery
Regulation of Oligodendrocyte Diffe
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DOI: 10.1126/science.1190927
, 779 (2010);330Science
Ben Emery
Regulation of Oligodendrocyte Differentiation and Myelin
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The myelin sheath was not stained in these
preparations, thus the existence of a continual
cytoplasmic link between oligodendrocytes and
myelin was not demonstrated until the advent of
electron microscopy.
Silver-stained oligodendrocytes (“O”) and a neuroglia/astrocyte (“N”)

Discovering Myelination
Nonmyelinating (Remak-type) Schwann cell engulfs multiple axons of a diameter below 1 μm
Schwann cell elaborates myelin ensheathing one axonal segment Oligodendrocytes ensheathing multiple axonal segments
Electron-dense intraperiod lines (IPL)
Major dense lines (MDL) Schmidt-Lanterman incisures (SLI)
provide cytosolic channels
Radial components
Adhesive tight junction

Discovering Myelination
Schematic depiction as unrolled to visualize structural specializations
Antibodies speciﬁc for
1. Axonal sodium channel Nav1.6 ( green)
2. Myelin-associated glycoprotein (MAG, orange)
Marker for Schmidt-Lanterman incisures
3. Nucleus of the Schwann cell (blue)
Illustrating the dimension of the myelin unit
Fig. Dissection from the sciatic nerve

Immature SCs surrounding axon bundles
Late embryonic development
OR
Shortly after birth
SCs extend processes into the bundles, selecting and extracting single axons
of large diameters (approx. >1 micrometer in the adult mouse) to achieve a
SC–axon relationship termed the pro-myelinating stage.
Radial axonal sorting
* Sox 10, Oct 6, Brn 2, YY1……All Transcrptionfactors
Radial axonal sorting
Review
Molecular mechanisms regulating
myelination in the peripheral nervous
system
Jorge A. Pereira, Fre´de´ric Lebrun-Julien and Ueli Suter
Institute of Cell Biology, Department of Biology, Swiss Federal Institute of Technology, ETH Zu¨ rich, CH-8093 Zu¨ rich, Switzerland
Glial cells and neurons are engaged in a continuous and
highly regulated bidirectional dialog. A remarkable ex-
largely due to the relative anatomical simplicity of periph-
eral nerves and the consequential experimental opportu-
Review
Trends in Neurosciences February 2012, Vol. 35, No. 2
Transcriptional control of Myelination in PNS
Myelination in PNS

Epigenetic control of Myelination in PNS
Review
Review
system
ample is the control of myelination. Oligodendrocytes in
nities. Although there are signiﬁcant molecular differences
Review
Review Trends in Neurosciences February 2012, Vol. 35, No. 2
• Sox10 recruits both HDAC1 and HDAC2 to regulatory regions of the Sox10 and Krox20 loci
• In vitro studies showed that miRNA 29a regulates expression of the dosage-sensitive hereditary neuropathy-causing PMP22
• Cell cycle exit help differentiation
• MicroRNAs required for minor extent in Radial sorting

Transcriptional and epigenetic control of PNS myelination
Sox10
(SRY-related HMG- box-10)
Oct6
(octamer-binding transcription factor-6)
Activate Synergistically induce Krox20/Egr2
(early growth response-2)
1. Activate numerous myelin genes
2. Suppress myelination inhibitors
3. Maintain the myelinated state
NFATc4
(nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent-4)
Associates with Sox10 to activate 1. Krox20
2. P0 (protein-zero) genes
Encodes
PNS myelin protein Myelin lamellae compaction and stability
Yy1 (Yin yang-1)
Regulates
Important for Myelination
NRG1 type III (NRG1-III) NF-kB
(nuclear factor of k light poly- peptide gene enhancer in B cells)
Deacetylation
Histone deacetylases HDAC1 and HDAC2
Sox10
activate activate

SREBP cleavage-activating protein
(SCAP)
Sterol regulatory element-binding proteins
(SREBPs)
activate
deletion
Cholesterol and fatty acid synthesis Altered myelin synthesis
Severe hypomyelination with uncompacted myelin stretches
• Animal Model for PMP22 (peripheral myelin protein-22) based inherited peripheral neuropathies : Reduced
expression of genes involved in cholesterol biosynthesis
Lpin1
Phosphatidate phosphatase (PAP1) Triacylglycerol biosynthesis
deletion
Phosphatidic acid MEK–Erk pathway
*MEK = Mitogen-activated protein kinase
Erk = Extracellular-signal regulated kinase
Accumulation
activate
Demyelination

Selection of axons and initiation of contact
• A minimum calibre is required (~1 µm)
• How axons of a minimum calibre are selected for myelination is still not understood
Certain cell adhesion molecules
L1 NCAM (neural cell adhesion molecule)
Polysialylated NCAM
Expressed on unmyelinated axons
Downregulated during axonal myelination
Nerve growth factor (NGF)
Activate
Tyrosine kinase TrkA receptors
Autophosphorylation
Cause

Binding of various adaptor proteins
Phospholipase C-γ1 (PLCγ1)
Src homology 2 domain-containing transforming protein (SHC)
Phosphatidyl-inositol 3–kinase (PI3K)
Extracellular signal-regulated kinase 1 (ERK1)
Signaling Pathways Converge into Nucleus
Cause
Transcription of neuronal genes that can modulate the ability of oligodendrocytes and Schwann cells to myelinate

Axo–glial contact and formation of the node
3 Junctions in a Neuron
Paranodal domain Nodal domain Juxtaparanode
Axo–glial junction between
myelin and the axolemma
Caspr (contactin- associated protein/paranodin)
contactin, neurofascin 155 (Nfasc155)
Nfasc186 (a neuronal isoform of neurofascin)
ankyrin G
neural–glial-related cell adhesion molecule (NrCAM)
βIV-spectrin
MECHANISMS OF AXON
ENSHEATHMENT AND MYELIN
GROWTH
Diane L. Sherman and Peter J. Brophy
Abstract | The evolution of complex nervous systems in vertebrates has been accompanied by,
and probably dependent on, the acquisition of the myelin sheath. Although there has been
substantial progress in our understanding of the factors that determine glial cell fate, much less
R E V I E W S
Centre for Neuroscience
Research, University of
Edinburgh, Summerhall,
Edinburgh EH9 1QH, UK.
Correspondence to P.J.B.
e-mail:
peter.brophy@ed.ac.uk
doi:10.1038/nrn1743
nerve impulse conduction. During vertebrate evolu-
tion this has been achieved through the development
of myelin-forming glial cells — oligodendrocytes in the
CNS, and Schwann cells in the PNS. These cells wrap
around axons so that the molecular machinery respon-
sible for propagating action potentials is concentrated
at regular, discontinuous sites along the axon. These are
known as nodes of Ranvier. The presence of myelin as
aninternodalinsulatorensuresthatmembranedepolar-
ization can only occur at the nodes. The result is rapid,
saltatory (from the Latin saltare, to jump, or to dance)
nerve conduction.
Themyelinsheathisoneofthebeststudiedmamma-
lian membranes, not least because of its vital function,
and also owing to its abundance and the ease of isola-
tion of enriched myelin fractions. Consequently, there
is a vast literature on the biochemical and biophysical
properties of this membrane in health and disease,
and considerable detail has been amassed about the
biosynthesis of its constituent lipids and proteins (for
a review, see REF. 1). Furthermore, and reflecting our
growingunderstandingof hownervoussystems develop
cursors have be
few years (for re
have revealed th
number of recep
tion factors in the
there has been, a
our understandi
from and which
In spite of thi
surprisingly little
and dynamics o
mine how the m
around axons in
slow in unders
nerves to contin
These are key q
system function
myelin as an ins
that myelin-form
of nodes of Ranv
demic interest, a
of repair and the
NATURE REVIEWS | NEUROSCIENCE
he involvement of a steadily increasing
ptor signalling pathways and transcrip-
edifferentiationofglialcells.Therefore,
and continues to be, steady progress in
ng of where myelin-forming glia come
molecules regulate their specification.
s burgeoning knowledge, until recently
e was known about the molecular basis
f the cell–cell interactions that deter-
yelin sheath is extended and stabilized
n the first place. Progress has also been
tanding the mechanisms that allow
nue growing in the postnatal animal.
questions for understanding nervous
n, as they relate directly to the role of
sulator of nerve fibres and to the way
ming glia participate in the assembly
vier. These issues are of more than aca-
s progress in revealing the mechanisms
e essential role of myelin-forming glia
VOLUME 6 | SEPTEMBER 2005 | 683

Myelination causes clustering of the sodium channel complex at nodes of Ranvier and axon initial segments
MECHANISMS OF AXON
GROWTH
R E V I E W S
e-mail:
doi:10.1038/nrn1743
nerve conduction.
growingunderstandingof hownervoussystems develop
cursors have bee
few years (for re
have revealed th
number of recep
tion factors in the
there has been, a
our understandin
from and which
In spite of this
surprisingly little
and dynamics o
mine how the m
around axons in
slow in underst
nerves to contin
These are key q
system function
myelin as an ins
that myelin-form
of nodes of Ranv
demic interest, as
of repair and the
NATURE REVIEWS | NEUROSCIENCE
e involvement of a steadily increasing
tor signalling pathways and transcrip-
edifferentiationofglialcells.Therefore,
and continues to be, steady progress in
the first place. Progress has also been
uestions for understanding nervous
n, as they relate directly to the role of
sulator of nerve fibres and to the way
vier. These issues are of more than aca-

w
Review
system
Review
Schwann Cell – Axon interactions

Myelin process extension around target axons
Contains a high percentage of lipids compared with the plasma membranes
Cholesterol is a major constituent
High galactolipid content
Ceramide Galactosyl Transferase (CGT)
Enzyme UDP galactose
Encodes
CNS PNS
Disrupted PARANODAL AXOGLIAL JUNCTIONS Lipids were replaced with glucoanalogs
Reduced nerve conduction velocity Normal nerve conduction
Myeline Membrane
Knock-Out
Stops Synthesis of galactolipids

Cerebroside sulphotransferase
Sulphated derivatives
CNS PNS
Disrupted PARANODAL AXOGLIAL JUNCTIONS Lipids were replaced with glucoanalogs
Reduced nerve conduction velocity Normal nerve conduction
Knock-Out
Stops Synthesis of galactolipids
Galactolipid

Involvement of other cytoskeletal element
Schwann cells
Oligodendrocytes
Rho kinase (ROCK)
phosphorylate
actin–myosin mechanical transduction
regulate
myosin light chains
Knock-Out Single myelinating process of the Schwann cell
splits to form many smaller internodes
Sphingosine 1-phosphate receptor 5
(S1P5, also known as EDG8)
High-afﬁnity sphingosine 1-phosphate receptor
restricted to
Oligodendrocytes

Stimulation of oligodendrocytes with sphingosine 1-phosphate
affect
two pathway
myelin process retraction cell survival
mediated through
Rho kinase–collapsin response-mediated
protein signalling pathway
Pertussis toxin-sensitive,
Akt (v-akt murine thymoma viral oncogene homologue)
dependent pathway
mediated through
Cdc42-Rac• Fyn extension
causeactivate
• myelinating Schwann cell–neuron co-cultures
cytochalasin D
myelination stops
disrupt Actin ﬁlament

Demyelination and Remyelination in PNS
* Notch, c-Jun……All Transcrptionfactors
w
Review
system
Review
• Remyelintion after development which are triggered
because of Disease and Injury are not same and different
Transcription factor activated during this process.

Myelination in CNS
Oligodendrocyteprogenitorcells

Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus
One of the hippocampal OPCs recorded by Bergles et al. ﬁlled with biocytin Antibodies against the OPC marker NG2
OPCs in the CA1 region were patch clamped and their membrane potentials measured in response to L- glutamate stimulation of CA3 neurons
*TTX = Tetrodotoxin
NATURE |VOL 405 |11 MAY 2000 |www.nature.com
..............................................
Glutamatergic synapses o
oligodendrocyte precursor
cells in the hippocampus
Dwight E. Bergles*, J. David B. Roberts², Peter So
& Craig E. Jahr*
* Vollum Institute, L474, Oregon Health Sciences Unive
Oregon 97201, USA
² MRC Anatomical Neuropharmacology Unit, Departm
University of Oxford, Oxford OX1 3TH, UK
...................................................................................................
Fast excitatory neurotransmission in the cen
occurs at specialized synaptic junctions betwe
high concentration of glutamate directly
channels. Low-af®nity AMPA (a-amino-3-hy
xazole propionic acid) and kainate glutamat
expressed by some glial cells1
, including oligo
sor cells (OPCs). However, the conditions that
of glutamate receptors on these non-neuronal
Here we report that stimulation of excita
hippocampus elicits inward currents in OPC
by AMPA receptors. The quantal nature of t
their rapid kinetics indicate that they are
exocytosis of vesicles ®lled with glutamat
these receptors. Some of these AMPA recepto
calcium ions, providing a link between axona
nal calcium levels in OPCs. Electron microscop
that vesicle-®lled axon terminals make synapti
NATURE |VOL 405 |11 MAY 2000 |www.nature.com
.................................................................
Glutamatergic synapses on
Dwight E. Bergles*, J. David B. Roberts², Peter Somogyi²
& Craig E. Jahr*
* Vollum Institute, L474, Oregon Health Sciences University, Portland,
Oregon 97201, USA
² MRC Anatomical Neuropharmacology Unit, Department of Pharmacology,
..............................................................................................................................................
Fast excitatory neurotransmission in the central nervous system
occurs at specialized synaptic junctions between neurons, where a
high concentration of glutamate directly activates receptor
channels. Low-af®nity AMPA (a-amino-3-hydroxy-5-methyl iso-
xazole propionic acid) and kainate glutamate receptors are also
expressed by some glial cells1
, including oligodendrocyte precur-
sor cells (OPCs). However, the conditions that result in activation
of glutamate receptors on these non-neuronal cells are not known.
Here we report that stimulation of excitatory axons in the
hippocampus elicits inward currents in OPCs that are mediated
by AMPA receptors. The quantal nature of these responses and
their rapid kinetics indicate that they are produced by the
exocytosis of vesicles ®lled with glutamate directly opposite
these receptors. Some of these AMPA receptors are permeable to
calcium ions, providing a link between axonal activity and inter-
nal calcium levels in OPCs. Electron microscopic analysis revealed
that vesicle-®lled axon terminals make synaptic junctions with the
8/8 groups of cells).
Paired stimuli p
(P2/P1 = 1.7 6 0.1,
following the secon
facilitation of excit
a
c
Figure 1 Synaptic respons
clamp recording of membr
20 pA). b, Evoked respons
recorded in voltage-clamp
(membrane potential = -9
responses recorded from th
biocytin-®lled OPC. d, Mic
conjugated streptavidin. e,
d. Scale bars for c and d,
© 2000 Macmillan Magazines Ltd
letters to nature
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way from pyramidal neurons to OPCs in the mammalian hippo-
campus that is mediated by excitatory, glutamatergic synapses.
Oligodendrocytes in the mammalian central nervous system
develop from a population of precursor cells during late gestational
and early postnatal life2
, providing the insulating sheaths of myelin
11. Cesare, P. & McNaughton, P. A novel heat-activated current in nociceptive neurons and its
sensitization by bradykinin. Proc. Natl Acad. Sci. USA 93, 15435±15439 (1996).
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Supplementary information is available on Nature's World-Wide Web site (http://
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Acknowledgements
The authors would like to acknowledge P. Hayes, J. Nation, S. Pickering and C. David
technical assistance, and S. Rastan, F. Walsh, M. Geppert and D. Simmons for valuab
critique.
Correspondence or requests for materials should be addressed to J.B.D.
(e-mail: John_B_Davis@sbphrd.com).
...............................................................
Glutamatergic synapses on
Dwight E. Bergles*, J. David B. Roberts², Peter Somogyi²
& Craig E. Jahr*
* Vollum Institute, L474, Oregon Health Sciences University, Portland,
Oregon 97201, USA
² MRC Anatomical Neuropharmacology Unit, Department of Pharmacology

DOI: 10.1126/science.1190927
, 779 (2010);330Science
Ben Emery
Regulation of Oligodendrocyte
DOI: 10.1126/science.1190927
, 779 (2010);330Science
Ben Emery
Regulation of Oligodendrocyte Differentiation and
PDGF = Inhibit myelination promoting gene and maintain OPC at it’s undifferentiated state
Jagged = Expressed on neurons and act as inhibitor for OPC differentiation
Id2, Id4, Hes5, Sox6 = Repress myelin gene expression and maintain OPC at it’s undifferentiated state
Axonal release of ATP
Stimulate
Adjacent astrocytes Promyelination cytokine LIF
signals
Oligodendrocyte differentiation
Release
miR-219, miR-338 = Target genes that usually act to maintain OPCs in the undifferentiated state, including PDGFRa, Sox6, and Hes5
* still Id2 and Id4 are activated by Tcf4
HDAC

Two types of growth in Myelination
1. Radial 2. Lateral
iversity Hospital, 1211 Geneva, Switzerland
y of Go¨ ttingen, 37075 Go¨ ttingen, Germany
olecular Physiology of the Brain (CNMPB), 37075 Go¨ ttingen, Germany
4
is a multilayered
oligodendrocytes
wever, the underly-
ing have remained
roach of live imag-
genetics, we show
incorporated adja-
most tongue. Sim-
s extend laterally,
n of a set of closely
borated system of
e growing myelin
king to the leading
lose with ongoing
ened in adults by
idylinositol-(3,4,5)-
tes myelin growth.
of myelin as a multi-
elin outfoldings in
y of myelin biogen-
s are ensheathed with
ble and complex trans-
sen and Mirsky, 2005;
., 2008). More than 60
years after the seminal discovery demonstrating that myelin
is made by axon-associated glial cells, and not by the axon itself
(Ben Geren, 1954), the molecular mechanisms by which the
myelin sheath is wrapped around the axon are still largely
unknown. This is due in part to the physical limitations of visual-
izing membrane dynamics at the nanometer scale and the time
span involved (i.e., days in vivo). Even if it represents ‘‘textbook
knowledge’’ that oligodendrocytes wrap myelin around an axon
by steering a leading process that stays in close contact with the
axon, we have almost no experimental data to substantiate this
claim. Does the leading edge resemble a glial growth cone-like
extension related to the one that drives axonal outgrowth in
developing neurons? It has also become apparent that myelin
is a dynamically active structure (Young et al., 2013) that can pro-
vide metabolic support to associated axons (Fu¨ nfschilling et al.,
2012; Lee et al., 2012). However, it remains completely unclear
how molecules reach the innermost myelin layer, i.e., passing
through a multilamellar stack of membranes.
A number of different models have been proposed to explain
how a myelin sheath might form in development. According to
the ‘‘carpet crawler’’ model (Bunge et al., 1961, 1989), the oligo-
dendrocyte forms a process that broadens and extends along
the entire axonal segment (the future internode) before it makes
one turn and moves underneath the growing sheet. However, at
least in the CNS, several morphological features of myelin are
incompatible with this model. In particular, it is clear from elec-
tron microscopic analysis that the number of myelin layers can
vary along the length of a single myelin sheath during its forma-
tion (Knobler et al., 1976). Moreover, the molecular forces neces-
sary to continuously displace myelin by newly made layers of
membrane from underneath might be too high. Some of these
shortcomings were reconciled in the ‘‘liquid croissant’’ (Sobottka
Cell 156, 277–290, January 16, 2014 ª2014 Elsevier Inc. 277
Myelin Membrane Wr
by PI(3,4,5)P3-Depend
Growth at the Inner T
Nicolas Snaidero,1,2 Wiebke Mo¨ bius,3,12 Tim Czopka,4,5,6,
Sandra Goebbels,3 Julia Edgar,3 Doron Merkler,9,10,11 Dav
1Max Planck Institute of Experimental Medicine, Cellular Neuroscie
2Department of Neurology, University of Go¨ ttingen, Robert-Koch-S
3Department of Neurogenetics, Max Planck Institute of Experiment
4Centre for Neuroregeneration
5MS Society Centre for Translational Research
6Euan Mac Donald Centre for Motor Neurone Disease Research
University of Edinburgh, Edinburgh EH16 4SB, UK
7MRC Centre for Regenerative Medicine, University of Edinburgh,
8FEI Company, Achtseweg Noord 5, 5651 GG Eindhoven, The Net
9Department of Pathology and Immunology, University of Geneva,
10Division of Clinical Pathology, Geneva University Hospital, 1211 G
11Department of Neuropathology, University of Go¨ ttingen, 37075 G
12Center for Nanoscale Microscopy and Molecular Physiology of th
*Correspondence: msimons@gwdg.de
http://dx.doi.org/10.1016/j.cell.2013.11.044
Myelin Membrane Wrapping of CNS Axons
by PI(3,4,5)P3-Dependent Polarized
Growth at the Inner Tongue
Nicolas Snaidero,1,2 Wiebke Mo¨ bius,3,12 Tim Czopka,4,5,6,7 Liesbeth H.P. Hekking,8 Cliff Mathisen,8 Dick Verkleij,8
Sandra Goebbels,3 Julia Edgar,3 Doron Merkler,9,10,11 David A. Lyons,4,5,6 Klaus-Armin Nave,3 and Mikael Simons1,2,*
1Max Planck Institute of Experimental Medicine, Cellular Neuroscience, Hermann-Rein-Strasse, 3, 37075 Go¨ ttingen, Germany
2Department of Neurology, University of Go¨ ttingen, Robert-Koch-Strasse, 40, 37075 Go¨ ttingen, Germany
3

Two types of growth in Myelination
cular Physiology of the Brain (CNMPB), 37075 Go¨ ttingen, Germany
s a multilayered
oligodendrocytes
ever, the underly-
g have remained
ach of live imag-
netics, we show
corporated adja-
st tongue. Sim-
extend laterally,
of a set of closely
orated system of
growing myelin
ng to the leading
se with ongoing
ed in adults by
ylinositol-(3,4,5)-
s myelin growth.
myelin as a multi-
n outfoldings in
of myelin biogen-
are ensheathed with
and complex trans-
n and Mirsky, 2005;
2008). More than 60
years after the seminal discovery demonstrating that myelin
is made by axon-associated glial cells, and not by the axon itself
(Ben Geren, 1954), the molecular mechanisms by which the
myelin sheath is wrapped around the axon are still largely
unknown. This is due in part to the physical limitations of visual-
izing membrane dynamics at the nanometer scale and the time
span involved (i.e., days in vivo). Even if it represents ‘‘textbook
knowledge’’ that oligodendrocytes wrap myelin around an axon
by steering a leading process that stays in close contact with the
axon, we have almost no experimental data to substantiate this
claim. Does the leading edge resemble a glial growth cone-like
extension related to the one that drives axonal outgrowth in
developing neurons? It has also become apparent that myelin
is a dynamically active structure (Young et al., 2013) that can pro-
vide metabolic support to associated axons (Fu¨ nfschilling et al.,
2012; Lee et al., 2012). However, it remains completely unclear
how molecules reach the innermost myelin layer, i.e., passing
through a multilamellar stack of membranes.
A number of different models have been proposed to explain
how a myelin sheath might form in development. According to
the ‘‘carpet crawler’’ model (Bunge et al., 1961, 1989), the oligo-
dendrocyte forms a process that broadens and extends along
the entire axonal segment (the future internode) before it makes
one turn and moves underneath the growing sheet. However, at
least in the CNS, several morphological features of myelin are
incompatible with this model. In particular, it is clear from elec-
tron microscopic analysis that the number of myelin layers can
vary along the length of a single myelin sheath during its forma-
tion (Knobler et al., 1976). Moreover, the molecular forces neces-
sary to continuously displace myelin by newly made layers of
membrane from underneath might be too high. Some of these
shortcomings were reconciled in the ‘‘liquid croissant’’ (Sobottka
Cell 156, 277–290, January 16, 2014 ª2014 Elsevier Inc. 277
Myelin Membrane Wra
by PI(3,4,5)P3-Depende
Growth at the Inner To
Nicolas Snaidero,1,2 Wiebke Mo¨ bius,3,12 Tim Czopka,4,5,6,7 L
Sandra Goebbels,3 Julia Edgar,3 Doron Merkler,9,10,11 David
1Max Planck Institute of Experimental Medicine, Cellular Neuroscienc
2Department of Neurology, University of Go¨ ttingen, Robert-Koch-Stra
3Department of Neurogenetics, Max Planck Institute of Experimental
5MS Society Centre for Translational Research
6Euan Mac Donald Centre for Motor Neurone Disease Research
University of Edinburgh, Edinburgh EH16 4SB, UK
7MRC Centre for Regenerative Medicine, University of Edinburgh, Ed
8FEI Company, Achtseweg Noord 5, 5651 GG Eindhoven, The Nethe
9Department of Pathology and Immunology, University of Geneva, 12
10Division of Clinical Pathology, Geneva University Hospital, 1211 Ge
11Department of Neuropathology, University of Go¨ ttingen, 37075 Go¨ t
12Center for Nanoscale Microscopy and Molecular Physiology of the
*Correspondence: msimons@gwdg.de
http://dx.doi.org/10.1016/j.cell.2013.11.044
Myelin Membrane Wrapping of CNS Axons
by PI(3,4,5)P3-Dependent Polarized
Growth at the Inner Tongue
Nicolas Snaidero,1,2 Wiebke Mo¨ bius,3,12 Tim Czopka,4,5,6,7 Liesbeth H.P. Hekking,8 Cliff Mathisen,8 Dick Verkleij,8
Sandra Goebbels,3 Julia Edgar,3 Doron Merkler,9,10,11 David A. Lyons,4,5,6 Klaus-Armin Nave,3 and Mikael Simons1,2,*
1Max Planck Institute of Experimental Medicine, Cellular Neuroscience, Hermann-Rein-Strasse, 3, 37075 Go¨ ttingen, Germany
2Department of Neurology, University of Go¨ ttingen, Robert-Koch-Strasse, 40, 37075 Go¨ ttingen, Germany
3Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Hermann-Rein-Strasse, 3, 37075 Go¨ ttingen, Germany

Synthesis of myelin basic protein (MBP)
microRNAs
ribosomes
MBP mRNA
microtubule
MECHANISMS OF AXON
GROWTH
is known about the cellular mechanisms that determine how the myelin sheath is extended and
R E V I E W S
e-mail:
doi:10.1038/nrn1743
Functional integration of the vertebrate nervous
system’s byzantine cytoarchitecture requires rapid
nerve conduction.
growing understanding of how nervous systems develop
in general, the embryonic origins and cell lineages of
oligodendrocytes and Schwann cells and their pre-
cursors have been more clearly defined over the past
few years (for reviews, see REFS. 2,3). These discoveries
have revealed the involvement of a steadily increasing
number of receptor signalling pathways and transcrip-
tion factors in the differentiation of glial cells. Therefore,
there has been, and continues to be, steady progress in
our understanding of where myelin-forming glia come
from and which molecules regulate their specification.
In spite of this burgeoning knowledge, until recently
surprisingly little was known about the molecular basis
and dynamics of the cell–cell interactions that deter-
mine how the myelin sheath is extended and stabilized
around axons in the first place. Progress has also been
slow in understanding the mechanisms that allow
nerves to continue growing in the postnatal animal.
These are key questions for understanding nervous
system function, as they relate directly to the role of
myelin as an insulator of nerve fibres and to the way
that myelin-forming glia participate in the assembly
of nodes of Ranvier. These issues are of more than aca-
demic interest, as progress in revealing the mechanisms
of repair and the essential role of myelin-forming glia
is known about the cellular mechanisms that determine how the myelin sheath is extended and
stabilized around axons. This review highlights four crucial stages of myelination, namely, the
selection of axons and initiation of cell–cell interactions between them and glial cells, the
establishment of stable intercellular contact and assembly of the nodes of Ranvier, regulation
of myelin thickness and, finally, longitudinal extension of myelin segments in response to the
lengthening of axons during postnatal growth.
NATURE REVIEWS | NEUROSCIENCE VOLUME 6 | SEPTEMBER 2005 | 683
mbryonic origins and cell lineages of
es and Schwann cells and their pre-
en more clearly defined over the past
views, see REFS. 2,3). These discoveries
e involvement of a steadily increasing
tor signalling pathways and transcrip-
e differentiation of glial cells. Therefore,
nd continues to be, steady progress in
the first place. Progress has also been
uestions for understanding nervous
, as they relate directly to the role of
ulator of nerve fibres and to the way
ier. These issues are of more than aca-
e nodes of Ranvier, regulation
segments in response to the
Basic myelin protein binds to negative surface of plasma membrane

Radial Axonal Sorting
Immune-Electron microscopy of P3-P4 mouse sciatic nerves
4025RESEARCH ARTICLE
Development 138, 4025-4037 (2011) doi:10.1242/dev.065490
© 2011. Published by The Company of Biologists Ltd
SUMMARY
Radial sorting allows the segregation of axons by a single Schwann cell (SC) and is a prerequisite for myelination during
Non-redundant function of dystroglycan and 1 integrins in
radial sorting of axons
Caterina Berti1,
*,†
, Luca Bartesaghi1,
*,‡
, Monica Ghidinelli1
, Desirée Zambroni1
, Gianluca Figlia1,3
,
Zu-Lin Chen2
, Angelo Quattrini3
, Lawrence Wrabetz1
and M. Laura Feltri1,§
RESEARCH A
amultistep
Itinvolves
onsignals
includethe
matrixsignals
11)via1
fcongenital-
mpairedinthe
andismildly
ndJenkison,
Bycontrast,
istaldistricts
bothlaminin
stricts(Chen
asonsforthis
derivefrom
minins.
Deletionofreceptorscontainingthe1integrinsubunitcauses
arrestinradialsortingdistally,butonlymilddefectsproximally
(Feltrietal.,2002),leavingthelamininreceptorinvolvedinradial
sortinginspinalrootsunidentified.Radialsortingdefectsarealso
observedinmodelsofotherhumanmusculardystrophies(MDC1D
andFukuyama)thataretheresultofmutationsinfukutinor
LARGEglycosyltranferases(Levedakouetal.,2005;Saitoetal.,
2007),whichhave-dystroglycanassubstrate.Thesedatasuggest
eitherthatdystroglycanmediatessortingorthatthese
glycosyltransferasesactonotherproteins,suchas1integrins.
However,theabsenceofLargeorfukutindoesnotimpair
glycosylationof1integrin(Levedakouetal.,2005;Saitoetal.,
2007)anddeletionofdystroglycaninSCsdoesnotaffectradial
sorting,atleastindistalnerves(Saitoetal.,2003).Thus,the
molecularmechanismsbywhichthesemutationsaltersortingare
unknown.
Finally,themechanismsbywhichdifferentlaminin-receptor
pairspromotesortingareincompletelyunderstood.Axonalsorting
requiresmultipleevents:theformationof‘families’ofSCswith
multipleaxonscontainedinacommonbasallamina(Websteretal.,
1973),thematchingofthenumberofaxonsandSCs,theinsertion
ofSCprocessesaroundaxonstorecognizeandsegregatelarge
ones,andthedefasciculationofsingleaxonswiththeirown
daughterSCandbasallamina(MartinandWebster,1973;Webster
etal.,1973).Itisunknownwhichlaminin-receptorpairscontribute
toeachstep.Forexample,lamininspromotetheformationofSC
processesandtheinteractionwithaxons(Yuetal.,2009)via
activationofRac1bya1integrinreceptor(Benningeretal.,
2007;Nodarietal.,2007),butlamininsalsopromoteSC
proliferationandsurvivalviaactivationofPi3K,FakandCdc42
e,20132
llerUniversity,
eScientific
rkUniversity,
non27,1005,
DEVELOPMENT4025RESEARCH ARTICLE

Radial Axonal Sorting
4025RESEARCH ARTICLE
SUMMARY
Non-redundant function of dystroglycan and 1 integrins in
radial sorting of axons
Caterina Berti1,
*,†
, Luca Bartesaghi1,
*,‡
, Monica Ghidinelli1
, Desirée Zambroni1
, Gianluca Figlia1,3
,
Zu-Lin Chen2
, Angelo Quattrini3
, Lawrence Wrabetz1
and M. Laura Feltri1,§
RESEARCH A
samultistep
Itinvolves
sonsignals
sincludethe
matrixsignals
11)via1
.
ofcongenital-
mpairedinthe
andismildly
andJenkison,
Bycontrast,
distaldistricts
fbothlaminin
istricts(Chen
easonsforthis
derivefrom
aminins.
Deletionofreceptorscontainingthe1integrinsubunitcauses
arrestinradialsortingdistally,butonlymilddefectsproximally
(Feltrietal.,2002),leavingthelamininreceptorinvolvedinradial
sortinginspinalrootsunidentified.Radialsortingdefectsarealso
observedinmodelsofotherhumanmusculardystrophies(MDC1D
andFukuyama)thataretheresultofmutationsinfukutinor
LARGEglycosyltranferases(Levedakouetal.,2005;Saitoetal.,
2007),whichhave-dystroglycanassubstrate.Thesedatasuggest
eitherthatdystroglycanmediatessortingorthatthese
glycosyltransferasesactonotherproteins,suchas1integrins.
However,theabsenceofLargeorfukutindoesnotimpair
glycosylationof1integrin(Levedakouetal.,2005;Saitoetal.,
2007)anddeletionofdystroglycaninSCsdoesnotaffectradial
sorting,atleastindistalnerves(Saitoetal.,2003).Thus,the
molecularmechanismsbywhichthesemutationsaltersortingare
unknown.
Finally,themechanismsbywhichdifferentlaminin-receptor
pairspromotesortingareincompletelyunderstood.Axonalsorting
requiresmultipleevents:theformationof‘families’ofSCswith
multipleaxonscontainedinacommonbasallamina(Websteretal.,
1973),thematchingofthenumberofaxonsandSCs,theinsertion
ofSCprocessesaroundaxonstorecognizeandsegregatelarge
ones,andthedefasciculationofsingleaxonswiththeirown
daughterSCandbasallamina(MartinandWebster,1973;Webster
etal.,1973).Itisunknownwhichlaminin-receptorpairscontribute
toeachstep.Forexample,lamininspromotetheformationofSC
processesandtheinteractionwithaxons(Yuetal.,2009)via
activationofRac1bya1integrinreceptor(Benningeretal.,
2007;Nodarietal.,2007),butlamininsalsopromoteSC
proliferationandsurvivalviaactivationofPi3K,FakandCdc42
ute,20132
fellerUniversity,
eleScientific
orkUniversity,
ugnon27,1005,
DEVELOPMENT4025RESEARCH ARTICLE

• Understanding Biomechanical Pathway which triggers genes
• Understanding MBP mRNA transport
• Understanding Remyelination
• Treatment of disease such as Leukodystrophies, Neuropathy, Multiple sclerosis
• OPC response to Neuron excitation : Myelin Plasticity
*Myelination in the human brain can be triggered by functional activity, including reading, practicing the piano, and juggling .
(Bengtsson et al. 2005, Keller & Just et al. 2009, Liu et al. 2012, Scholz et al. 2009)
*In adult rodents, the training of even simple motor tasks stimulates myelination dependent on the region.
(Sampaio-Baptista et al. 2013)
*Social isolation negatively impacts myelination in both pubescent and adult mice.
(Makinodan et al. 2012) (Liu et al. 2012)
Future Advancement

Thank You
Oops!! I am naked
Yeah!! Now I am clothed
Thanks to oligo
and Schwanny

Myelination

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