Myelin components

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Myelin & Schwann Cell Components

Myelin
Axon relations
Diseases
Domains
Glycoproteins
Other components
Pathology: Images
Structure
Cross-section
Longitudinal
Schmidt-Lanterman cleft
Early images
Node of Ranvier
Schwann cell
Development
Mature
Myelinating
Non-myelinating
Components
Other

Schwann Cells: Original Description

Theodor Schwann

Myelin: Early Images
Leeuwenhoek, A. van, 1719 ⁷ Spinal Nerve: From cow or sheep	Ranvier, L., 1872 ⁸ Node of Ranvier: Rabbit	Ramon y Cajal 1909 Myelin Internode

Schwann Cell Development ²

Neural crest cells
Schwann cell: Types
Precursor
Immature
Mature
Myelinating
Non-myelinating (Remak)
Perisynaptic
Autophagic
Wallerian Degeneration
Denervation
Büngner bands
Images

Types: Developmental, Mature & Pathology ³

General: Proteins in Schwann cells
- Present at several stages
  - All stages of development: Sox10
  - Early stages: α4 integrin; AP2α; NCAD
  - During & after Immature stage: S100β
- Related to Schwann cell type
  - Myelin clearance: c-jun
  - Repair cell survival: Stat3
  - Sensor of axon damage & Repair cells: Mitf localization (Controlled by mTorc2)

Neural crest cells
- Anatomy
  - Originate from: Dorsal-most region of developing neural tube
  - Migrate: Ventrally && Dorsolaterally
- Multipotent progenitors
  - Differentiate into Schwann cell precursors: Regulated by
    - Transcription factors: SOX10; PAX3
    - Histone deacetylases 1 & 2 (HDAC1/2)
    - Axonal Neuregulin 1 (NRG1)
  - Also precursors for
    - Neurons: Peripheral nerve - Sensory & Sympathetic
    - Muscle: Skeletal & Cardiac
    - Systemic: Melanocytes; Connective tissue
- Migrate out: Contact developing axons
- Associate with: Extracellular matrix
- Antigens & Molecules
  - Not present on immature Schwann cells
    - Integrin-α4
    - AP2α
    - N-cadherin (NCAD; Cadherin-2)
  - Also present on immature Schwann cells
    - ERBB3
    - L1CAM
    - p75^NTR (NGFR)
    - SOX10
      - Required for Schwann cell Differentiation, Development & Myelination
      - Deletion: No formation of peripheral glia
- Neuregulin-1 mediated survival: Extracellular matrix dependent
Schwann cell precursor
- Differentiate into: Immature Schwann cells; Many other cell types
- Survival & Proliferative response: Neuregulin-1 pathways
  - Source: From Axons
  - NRG1 type III: Best characterized isoform
    - Axon tethered NRG1 type III: Processed by BACE1 to allow ERBB3 binding
    - NRG1-III haploinsufficiency: Hypomyelination
    - NRG1-III overexpression: Hypermyelination
  - Receptors (ERBB): Heterodimers composed of ErbB2 with either an ErbB3 or ErbB4
  - Neuregulin-1 actions
    - Signals regulate survival, proliferation, motility & differentiation of Schwann cell lineage
    - May also be involved in signalling from Schwann cell to axon
    - Clustering of AChRs at NMJs: Signals via glial cells
    - Muscle spindles: Induction & Differentiation
  - ERBB2 : Mutations
    - Pre-migratory Schwann cell progenitors are present near the dorsal root ganglia
    - Fail to move onto outgrowing spinal axons
    - Similar pattern to Neuregulin-1 mutations
  - ERBB3 deficient mice
    - Lack: Schwann-cell precursors & Schwann cells
    - Lose Sensory & Motor neurons: During 2nd half of embryonic development
  - ERBB4
    - Postsynaptic target of NRG1
    - Model: Dominant-negative ErbB4 receptor in nonmyelinating Schwann cells
      - Peripheral neuropathy
      - Schwann cells: Proliferation & Death
      - Unmyelinated axons: Loss; Hot & Cold pain insensitivity
- Molecular markers
  - Distinctive to SC precursors: Cad 19
  - Also present on neural crest cells
    - Integrin-α4
    - AP2α
    - N-cadherin (NCAD; Cadherin-2)
  - Also present on immature Schwann cells
    - BFABP (FABP-7)
    - Desert Hedgehog (DHH)
    - P₀
    - Growth-associated protein 43 (GAP-43)
    - PMP22
    - PLP
- Timing of maturation of Schwann cell precursors: Regulated by endothelins
- Differentiation markers: P₀; Growth-associated protein 43 (GAP-43); Spondin-1
- Trophic support for other cells
  - ? Promote motor neuron & DRG cell survival
  - ? via GDNF, or Neurotrophin 3 (NT3)
Immature Schwann cells
- Precursor SC → Immature SC differentiation: Driven by
  - NOTCH signalling
  - Reduced transcriptional activity of AP2α & Endothelin B (EDNRB)
- Differences from Schwann cell precursors
  - No dependence on NRG1 signal for survival
  - Autocrine support of survival via
    - Neurotrophin 3 (NT3)
    - Insulin-like growth factor 2 (IGF2)
    - Platelet-derived growth factor BB (PDGF-BB)
  - Molecules & features present on immature SC
    - GFAP
    - S100
    - OCT6
    - O4 glycolipid antigen
    - NCAM
    - P0
    - Presence of basal lamina
  - Molecules absent on immature SC
    - Cad 19
    - Integrin-α4
    - AP2α
    - Ncad
- Molecules on Immature SC and Myelinating & Non-myelinating Schwann cells
  - S100 antigen in cytoplasm
  - O4 glycolipid antigen
- Trophic support for other cells
  - Connective tissue development: Perineurium; Epineurium
  - Nerve arteries
  - Trophic molecule: Desert Hedgehog
    - Human disease: Neuropathy with minifascicles & gonadal dysgenesis
  - Mouse model: Desert hedgehog knockout
    - Thin perineurium
    - Scanty epineurium
- Ensheath bundles of developing axons: "Radial Sorting"
  - Formation of one-to-one SC/axon segment relationship
  - Stepwise events: Sort out large caliber axons (> 1 μm) from axon bundles
    - SC deposition (& maturation) of basal lamina
    - Coordinated progression in cell cycle/proliferation: Regulated by
      - Laminin signals
      - Jun activation domain-binding protein 1 (JAB1)
    - Immature SCs actively protrude processes
      - Interdigitate among naked axons: Promote axon recognition or docking
      - Isolation of docked axons from the others ("locking")
      - Segregate locked axon outside bundles
      - Axon ensheathing & myelination

Mature Schwann cells

Immature SC → Non-proliferating promyelinating SC differentiation: Mechanisms
- Activation
  - OCT6 & BRN2 transcription factors
  - Chromatin remodelling complexes BAF/BRG1
- Repression of differentiation inhibitors
  - By zinc finger e-box-binding homeobox 2 (ZEB2)
  - EDNRB, SOX2, c-JUN, NOTCH
Myelinating Schwann cell
- 1st mature Schwann cell formed in development
- Precursor: Promyelinating Schwann cell
  - Forms association with one single axon
  - Differentiation driven by
    - ADCY6
    - GPR126
  - Development is blocked at this stage by
    - Inactivation of transcription factors: Egr2 or Oct6
      - Oct6: Delays myelination
      - Egr2: Schwann cells due to myelinate
        
        Envelop large-diameter axons
        
        Do not wrap around axons or form myelin
    - Antibodies to galactocerebroside
    - P₀ disorders: Mild overexpression, or Knock out
  - ? Involvement of other myelin transcription factors
- Promyelinating SCs → Myelinating SCs: Terminal differentiation
  - Involves zinc finger protein EGR2/KROX20
  - Coordinated activity of: OCT6, SOX10, YY1, NFATC4
  - Cofactors: NEB1/2
  - Recruitment: HDAC/NuRD & BRG1/BAF complexes
- Express
  - Myelin proteins: P₀; Myelin basic protein; PMP-22; MAG; Krox-20 (EGR2); Periaxin; Connexin-32 (GJB1)
  - Cholesterol biosynthetic enzymes: HMG Co-A reductase; Oleoyl-Co-A synthase
- Downregulated molecules
  - Neural cell-adhesion molecule (NCAM): Present on
    - Normal non-myelinating Schwann cells
    - Some adaxonal SC cytoplasm
  - Neurotrophin receptor, p75
  - Glial fibrillary acidic protein (GFAP)
- Trophic effects
  - Regulation of axonal structure & function
  - Schwann cell signal: Myelin-associated glycoprotein
  - ? Axon receives signal via kinase phosphatase cycle
  - Maintains phosphorylation of neurofilaments: Determines axonal caliber
- Transcription factors required for myelination
  - Krox-20 (EGR2)
  - SOX10
  - Zeb2
- Transcription factors related to timing of myelination
  - Oct-6 (SCIP; POU3f1)
  - Brn-2
  - NFκB
- Negative regulators of myelination: Induce SC dedifferentiation
  - Notch
  - c-Jun

Non-myelinating (Remak) Schwann cells

Formed later than myelinating Schwann cells
Expressed molecules
- Also on Immature Schwann cells
  - Neural cell-adhesion molecule (NCAM)
  - Neurotrophin receptor, p75
  - Glial fibrillary acidic protein (GFAP)
  - L1
  - GAP-43
  - A5E3
  - Ran-2
- Not on Immature Schwann cells
  - Galactocerebroside
  - α1β1 Integrin
- Telodendroglia (At NMJs) ⁹
  - TBX21
- On all Schwann cells
  - O4
  - S100
- Immature, but not mature, Schwann cells
  - MBP
  - c-Jun
Anatomy: Single Schwann (Remak) cells
- Normal: Surround several unmyelinated axons
- Axon loss
  - "Singletons"; Surround one unmyelinated axon
  - Express MBP without myelin

Perisynaptic Schwann cells
- Anatomy
  - Associate with axons at NMJs
  - Form loose cap over synaptic sites
- Play role in: Synapse formation & refinement
- Protein components
  - Receptors: Muscarinic; Purinergic
  - Channels: Ca⁺⁺
  - Schwann cell molecules
    - General: SOX10; S100β
    - Type related: NG2; p75NTR; LNX-1; Na_v1.6; TrkC; Nestin; P0; MAG; CNPase

Denervation: Mature Schwann cells lose contact with axons
- Nosology: Repair Schwann cells
- Precursors
  - Myelinating & Non-myelinating Schwann cells
- Molecular features ¹²
  - Transcriptional signalling
    - Epithelial to Mesenchymal transition (EMT)
    - Signalling Pathway: Phospholipid pathway system
      - Axon: Neuregulin-1
      - Schwann cell membrane: ErbB
      - Schwann cell: PI3K-PI5K-mTorc2
    - Sensor of axon damage & loss of Axon-SC contact: Mitf
      - Localization to nuclei
      - Increased levels
      - Mitf loss
        
        Axon degeneration: Accelerated
        
        Remyelination: Abnormal
    - Nrg1
      - Activates ErbB receptors on Schwann cells
      - Inhibits nuclear localization of Mitf
  - Myelin clearance: c-Jun
    - c-Jun loss: Reduced clearance of myelin debris after nerve injury
  - Maintaining repair cell survival: Stat3
- Stages related to axon pathology
  - Early: Wallerian degeneration
  - Late: Chronic axon loss
- Denervated Schwann cells: Features
  - Early
    - Myelinating Schwann cells develop phagocytic phenotype: Degrade myelin
  - Late
    - Form Büngner bands
    - Functions: Can guide & facilitate axon regeneration
    - Myelinating Schwann cells regress to cell type with similarities to, & differences from, immature Schwann cells
    - Protein components: NCAM; P0

Schwann cells & Myelin: Domains & Structure

Molecules in selective peripheral myelin & Schwann cell regions

Basal lamina: Laminin-2

Abaxonal Schwann cell membrane
- Dystroglycans, α & β
  - α Dystroglycan binds to basal lamina components: Laminin 2; Agrin
  - β Dystroglycan binds to
    - α Dystroglycan
    - Membrane components: Sarcoglycans β, δ, e
    - Intracellular molecules: Dystrophin-Dystroglycan-related protein 2; Dystrophin (Dp116); Utrophin
- α6β4 integrin
  - Expressed continuously along abaxonal membrane
  - Binds to Laminin 2
- Dystrophin-Dystroglycan-related protein 2 ⁵
  - Localized to blocks of SC cytoplasm directly apposed to myelin sheath
  - Binds to: β-Dystroglycan
- Periaxin
  - Complexed with: Dystrophin-Dystroglycan-related protein 2
  - Complex binds to: β-Dystroglycan
  - Mutations in CMT 4F
- Caveolin-1 : Localized in SC between blocks of DRP2 & in Perinuclear region
- Microvilli
  - Location: Outer borders of Schwann cell membrane; at nodes of Ranvier
  - Components: F-actin; Ezrin ; Radixin ; Moesin
  - Function: ? Associated with clustering of voltage-gated Na⁺ channels at nodal axolemma
Myelin domains
- Compact: P₀; Myelin basic protein ; PMP-22
- Non-compact
  - Components: MAG; DM20; E-cadherin; Connexin-32; Claudin
  - Locations: Paranodes; Schmidt-Lanterman incisures
- Also see: Molecular illustrations
Adaxonal Schwann cell membrane: Myelin-associated glycoprotein
Junctions: Between Schwann cell membrane
- Adherens
  - More numerous at outer incisures & paranodes
- Tight
  - Continuous double band along Schwann cell membrane
  - Locations: Paranodal SC membranes; Schmidt-Lanterman incisures
- Gap
  - Location: Between rows of tight junctions
  - More numerous at inner incisures & paranodes
Schmidt-Lanterman Clefts (Incisures)
- Anatomy
  - Communication between adaxonal & abaxonal Schwann cell cytoplasm
  - Channels: Run transxversely through spiral layers of compact myelin
  - Regions of Non-compacted myelin
  - Cytoplasm: Granular; May contain microtubules
  - Length: 13 μM
  - Frequency
    - Largest myelinated axons: 35 clefts/mM
    - Small myelinated axons: 8 clefts/mM
- Components: Similar to microvilli on abaxonal Schwann cell membrane
  - F-actin
  - Ezrin
  - Radixin
  - Moesin
  - MAG
  - Connexin-32
  - PTPLA6
- Pathology
  - Wallerian degeneration: Initial myelin ovoid consists of myelin between clefts
  - POEMS: Loss of myelin compaction often begins at Schmidt-Lanterman incisures
  - MAG neuropathy: Increased numbers
  - Images

Myelin Glycoproteins ¹

Glycoprotein	Properties
P₀	Location: Compact PNS myelin; Promyelinating Schwann cells; Büngner bands Abundant: 50% of PNS myelin proteins Molecular: Contains sulfated N-glycans; 30-kDa Function: Stabilizes intraperiod line of compact PNS myelin by homophilic interactions Diseases: CMT 1B; Dejerine-Sottas (CMT III); Congenital Hypomyelinating neuropathy
Myelin associated glycoprotein	Locations CNS > PNS Cells: Myelin-forming oligodendrocytes & Schwann cells Membranes: Periaxonal Schwann cell; ? Abaxonal Molecular: 100 kDa N-linked glycosylation: 30% by weight; Contain sialic acid, sulfate & GlcNAc Binds to α2,3-linked sialic acids Function: Axon-Glia interactions; Schmidt-Lanterman clefts Disease: Anti-MAG neuropathy
Peripheral myelin protein-22 (PMP-22)	Location: Compact PNS myelin Molecular: 22-kDa Similar to PLP/DM-20 & OTM in CNS 4 hydrophobic transmembrane domains Forms complexes with P0 in myelin membranes Disease: CMT 1A
170 kDa glycoprotein (SAG)	PNS Schwann cells & myelin
Schwann cell myelin protein (SMP)	Homology to MAG ? present in humans
Myelin/Oligodendrocyte glycoprotein (MOG)	Location: External surface of oligodendrocytes & CNS myelin
Oligodendrocyte-myelin glycoprotein (OMgp)	Location: CNS myelin
General properties Many are members of immunoglobulin superfamily Often express HNK-1 carbohydrate epitope Carbohydrate epitope may be involved in homophilic cell-cell interactions Glycosylation PNS: Major myelin proteins glycosylated CNS: Major myelin proteins not glycosylated

Nodes of Ranvier & Associated Structures ⁶

Myelinated Axons: Regions & Major components

Region	Axon		Myelin or Schwann cell
Region	Width	Proteins	Myelin or Schwann cell
Node of Ranvier	Narrow	Neurofascin 186 Na⁺ channels	SC Microvilli Gliomedin
Paranode	Narrow	CNTN1; Caspr1	Terminal loops Neurofascin 155
Juxtaparanode	Wide	Caspr2; CNTN2 K⁺ channels	Compact + Non-compact CNTN2
Internode	Wide	Necl1; Necl2	Compact SL clefts P0; MBP

Node of Ranvier

Anatomy
- Axon
  - Smaller diameter than at internode
  - Neurofilaments closely spaced
- Schwann cell microvilli contact axon
- CNS: Contact is formed by perinodal astrocyte
Schwann cell: Microvilli
- Membrane & Extracellular: Neurofascin (155 splice variant)
- Intracellular: Actin; Ezrin ; Radixin ; Moesin
- Other components
  - Gliomedin : Promotes node formation
  - Collagen V
  - Heparan sulfate proteoglycans
    - Syndecans
    - Versican (CSPG2)
Extracellular: Tenascin-C; Tenascin-R
Axon
- Membrane
  - Na⁺ channels
    - Voltage-gated
    - Types: Na_v1.6 > Na_v1.2, Na_v1.8, Na_v1.9
  - Other channel proteins: KCNK4; KCNQ2; KCNQ3
  - Cell adhesion molecules
    - Neurofascin (186 splice variant)
    - Nr-CAM
- Sub-membrane cytoskeleton
  - Ankyrin_G (ANK3) : 480 & 270 kDa splice variants
  - βIV-Spectrin (SPTBN4)
Images

Paranode

Anatomy
- Lateral edge of myelin sheath spirals around axon
- Axon & myelin sheath form axo-glial junctions
Paranodal Schwann cell membranes
- Connexin-32: Also present on Schmidt-Lanterman incisures
- E-cadherin
- Myelin-associated glycoprotein
- Neurofascin (155 splice variant)
- ITPR3
Paranodal axon membrane
- General
  - Anatomical components: Septate-like (Tight) junctions
- Cell adhesion molecules
  - Contactin-associated glycoprotein 1 (CASPR; CNTNAP1)
    - Heterodimer with contactin
    - Diseases
      - Hereditary: Arthrogryposis, distal
      - Immune: Immune neuropathy
  - Neurofascin
    - Disease: Immune PNS & CNS disorders
  - Contactin 1 (CNTN1)
    - Diseases
      - Immune neuropathy
      - Congenital myopathy
- NCP1 (Niemann-Pick, type C1 disease)
Axonal submembrane cytoskeleton
- Band 4.1B
- F-Actin
- Ankyrin_B (ANK2)
- αII/βII Spectrin

Juxtaparanode

Axon
- Anatomy: Axolemma extending 10 to 15 μM from paranode
- Axon membrane proteins
  - Voltage gated K+ channels: Delayed rectification
    - K_v1.1 (KCNA1): Episodic ataxia
    - K_v1.2 (KCNA2)
    - K_vβ2 (KCNB2)
  - Cell adhesion molecules
    - Contactin-associated protein-like 2 (CNTNAP2; Caspr2)
    - Contactin 2 (CNTN2; Tag1)
  - NCP2 (Nieman-Pick, type C2 disease)
- Axon submembrane proteins
  - Caspr2: PDZ domain
  - Band 4.1B
  - F-Actin
  - αII/βII Spectrin
Schwann cell membrane
- TAG1 (Contactin 2)
- K⁺ channels

Internodal region: Components

Axon
- Cell adhesion molecules
  - Necl1 (IGSF4B)
  - Necl2 (IGSF4)
Compact myelin
Schwann cell cytoplasm & membranes
- Contains tripartite strand with components similar to juxta paranode
- Strand apposes
  - Inner mesaxon
  - Inner region of Schmidt-Lanterman incisures
- Molecules
  - Necl4 (IGSF4C)
  - Necl2 (IGSF4)
  - MAG
Basal lamina

Axon Initial Segment

Excitatory neurons: Na_v1.2 (SCN2A)
Inhibitory neurons: Na_v1.1 (SCN1A)

Myelinated axon near Paranode & Node of Ranvier

Myelin-related components, Other

Peripheral myelin protein 2 (PMP2)
Myelin and Lymphocyte protein (MAL) family
- Connexin-32
  - 4 hydrophobic transmembrane domains
  - Disease: CMT-X
- Proteolipid protein/DM20
  - Mostly CNS
  - 4 hydrophobic transmembrane domains (4-TM): Homology to PMP-22
  - Most abundant protein in CNS myelin
  - Rabbit disorder: Paralytic tremor
  - Human disorders: Pelizaeus-Merzbacher & Spastic paraparesis
- Plasmolipin
  - Brain & Kidney
  - 4 hydrophobic transmembrane domains (4-TM)
  - Forms K⁺ specific, voltage-dependent channels when added to lipid bilayers
- Myelin vesicular protein (MVP17; Myelin and lymphocyte protein; MAL)
  - Distribution: Brain & Peripheral nerve; Epithelial cells in kidney & stomach
  - Schwann cell: Immature & Non-myelinating
  - 4 hydrophobic transmembrane domains (4-TM): Homology to PMP-22
  - Associated with glycosphingolipids in myelin
  - Mouse overexpression
    - Peripheral nerve
      - Separation of unmyelinated axons from bundles
      - Mild hypomyelination
    - CNS: Myelin change
    - Renal cysts
  - Knockout in PNS: Accelerated myelination
- PMP-22
Periaxin : CMT 4F (Dejerine-Sottas)
Myelin basic protein (MBP)
- Cytoplasmic
- Membrane-associated
- PNS
  - Present in: Compact myelin & Myelinating Schwann cells
  - MBP is 5% to 15% of myelin proteins
  - More abundant in myelin sheath of larger myelinated axons
- Disorders
  - rs12959006*T polymorphism: Higher risk of relapse in males with MS
  - Mouse model: shiverer
α6β4 integrin
Oligodendrocyte transmembrane protein (OTM)
- ? CNS homolog of PMP-22
- Mediator of parallel-array tight junction strands
- Also involved in spermatogenesis
Myelin transcription factor 1 (MYT1)
Cyclic nucleotide phosphodiesterase
E-cadherin
Acidic dipeptidase
95 kDa protein
80 kDa protein
QKI-6; QKI-7: Absent in quaking (hypomyelinating) mouse
Transcription factors: Null mutants non-myelinated
- SCIP/tst-1/Oct-6 : Earlier expression
- Krox-20 (EGR2)
Nodes of Ranvier
Necl4 (SynCAM 4)
- Location: Along internodes; Direct apposition to Necl1 on axons
- Important for mediating axon-glia contact during myelination in peripheral nerves
Neurite outgrowth inhibitor
- Expressed by oligodendroglia, not Schwann cells
- Inhibits neurite outgrowth: Via extracellular domain
Cholesterol biosynthetic enzymes
- HMG Co-A reductase
- Stearoyl-CoA desaturase (Oleoyl-Co-A synthase)
Glycolipids: Galactocerebroside; Sulfatide
- Null mutant by disrupting UDP-galactose ceramide galactosyltransferase
  - Normal myelin ultrastructure; Slow nerve conduction velocity
- Diseases
  - Krabbe
  - Metachromatic Leukodystrophy
Fatty acid: Oleic acid [C18:1 (n-9)] is the major fatty acid (~40%) in PNS myelin

Non-myelinating Schwann cells

Non-myelinating & Denervated Schwann cells: Components

Glial fibrillary acidic protein (GFAP)
Growth associated protein 43 kDa (GAP-43)
F-spondin (SPON1)
Low affinity neurotrophin receptor/p75 (p75^NTR; NGFR; TNFRSF16)
Neural cell adhesion molecule 1 (NCAM; CD56)
L1 cell adhesion molecule (L1CAM)
- Disease: MASA; Spastic paraparesis
N-syndecan (SDC3) : Binds to novel collagen in extracellular matrix
N-cadherin (CDH2)
Ninjurin (NINJ1)
PTPLA6
Amphiregulin
Myelin transcription factors
- PAX3
  - Disease: Waardenburg syndrome ± meningomyelocele
  - Interaction with SOX10
- c-jun
- Krox-24 (EGR1)
- Krox-20 (EGR-2)
  - Function: Required for myelination
  - Diseases: Hereditary Neuropathies
  - Knockout: Produces arrest of Schwann-cell myelination
- OCT6 : Knockout produces arrest of Schwann-cell myelination
- SOX family
  - SOX4
  - SOX5
  - SOX10
    - Modulates other myelin-related transcription factors & proteins: Connexin-32; P₀
    - Required for Schwann cell development & myelination
    - Disease: Hypomyelination in CNS & PNS
  - SOX13
Glycolipids: Galactocerebroside; Sulfatide
- Lower levels in denervated than non-myelinating Schwann cells

Other Schwann cell components

Dystrophin: Truncated Dp116
Utrophin
Dystroglycans α & β
Laminin a2
- Disease: Congenital muscular dystrophy
Agrin
S100 (β subunit) : Calcium binding protein; Cytoplasmic
Apolipoprotein E
Desert Hedgehog

Early growth response (EGR) genes

EGR1 (Krox-24; NGFIA)
- Zinc finger protein
EGR-2 (Krox-20)
- Zinc finger protein
- Mutations: Reduced expression of late myelin genes MBP & P₀
- Clinical syndromes: Hereditary Neuropathies
EGR-3
- Mouse knockout
  - Loss of spindles
  - Sensory ataxia
- Egr3 overexpression: Lethal
  - All myotubes differentiate into intrafusal phenotype & express Sd-MyHC

Myelin-Associated Glycoprotein (MAG; siglec-4) ^1,4

Characteristics of MAG protein
- Myelin glycoprotein
  - Abundance in myelin: CNS 1%; PNS 0.1%
- Family: siglec proteins
  - Sialic acid binding
    - Bind glycoconjugate ligands in sialic acid-dependent manner
    - α2,3-linked sialic acid
    - Also interact at least with three terminal monosaccharide units
    - Function similar to selectins
  - Immunoglobulin superfamily
  - Extracellular IgG domains: Amino terminal V-set, followed by C2-set
  - Most have functional roles in immune or nervous system
  - Other siglec family members
    - Sialoadhesin (siglec-1)
    - CD22 (siglec-2)
    - CD33 (siglec-3)
    - siglec-5
    - siglec-6
- 2 Isoforms
  - S-MAG
    - 67kD after deglycosylation
    - Predominant form in adult CNS & PNS
    - Cytoplasmic domain is zinc-binding protein
  - L-MAG
    - 72kD after deglycosylation
    - Absent from adult PNS
    - Different cytoplasmic domain than S-MAG
    - Plays role in formation of CNS myelin sheath
MAG Location
- Myelinated axons: Periaxonal regions
- Myelinating Schwann cells: Detectable after processes have turned around axon at least once
MAG Functions
- Stabilizes contacts between myelinating axons and glial processes
- Formation of morphologically intact myelin sheath
  - Schwann cell: Periaxonal cytoplasmic collar
  - Compact myelin structure
- Maintenance of myelin with aging in PNS
- Axonal
  - Maintenance of size
  - Inhibits axon regeneration in CNS: Binds to NOGO (NgR) with p75(NTR) coreceptor
  - MAG knockout mice: Neurofilament spacing characteristic of unmyelinated axons
- MAG 2nd messenger: Fyn nonreceptor-type tyrosine kinase
Disease
- Peripheral neuropathy with Serum IgM anti-MAG antibodies

Myelin/Oligodendrocyte Glycoprotein (MOG)

MOG protein
- Location: Oligodendrocytes; Schwann cells
  - Outermost myelin sheath layers
  - Oligodendrocyte cell surface
- Abundance: 0.05% of myelin proteins
MOG disorders
- Seum IgG antibodies in CNS > PNS Disorders (MOGAD) ¹¹
  - Test methodology: Cell based assays
  - CNS syndromes
    - Onset age: Child or Adult
    - Syndromes
      - Optic neuritis
      - Myelitis
      - Brainstem syndromes
      - Acute disseminated encephalomyelitis (ADEM): 50% of cases
      - Encephalitis
      - Central & Peripheral nervous system demyelination (CCPD)
      - Childhood CNS denyelinating disorders: Higher frequency than adults
    - Course
      - Relapsing in 50%
      - MOG antibodies: May be negative during remission
    - CNS MRI: Optic nerve enhancement, perineural: Spinal cord H-sign; T2-lesion resolution over time
  - PNS: Few patients ¹⁰
    - Frequency in Motor-Sensory neuropathies: 3%
    - CNS + PNS features: 40%
    - PNS demyelination: 60%
- Hereditary
  - Narcolepsy 7, Dominant

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References
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6. J Periph Nerv Sys 2002;7:1-12, Glia 2008;56:1532-1540
7. Leeuwenhoek, A. van, 1719. Epistola XXXII (p. 312) in Epistolae physiologicae super compluribus naturae arcanis, Adrianum Beman, Delft.
8. Ranvier, L., 1872. Recherches sur l�histologie et la physiologie des nerfs. Archives de Physiologie Normale et Pathologique, 4, 129-149.
9. Muscle Nerve 2021;64:109-115
10. Mult Scler Relat Disord 2022;68:104214
11. Front Neurol 2022;13:885218
12. Cell Rep 2023;42:113282

10/30/2024