Myelin components

Front, Search, Index, Links, Pathology, Molecules, Syndromes,
Muscle, NMJ, Nerve, Spinal, Ataxia, Antibody & Biopsy, Patient Info

MYELIN & SCHWANN CELL COMPONENTS

Myelin
Diseases
Domains
Glycoproteins
Other components
Structure, Cross-section
Node of Ranvier
Schwann cell
Components: Non-myelinating
Components: Other
Development

Theodor Schwann

Schwann cell development²

Developmental stages³
1. Neural crest cells
  - Differentiate into Schwann cell precursor cells
  - Migrate out to contact developing axons
2. Schwann cell precursor
  - Survival response to β-Neuregulin
    - Source: From axons
    - Response via ERBB3 receptor
    - ERBB3^-/- mice
      - Lack Schwann-cell precursors and Schwann cells
      - Lose most sensory and motoneurones during 2nd half of embryonic development
  - Timing of maturation of SC precursors: Regulated by endothelins
  - Differentiation markers: P₀; Growth-associated protein 43 (GAP-43); F-spondin
  - Trophic support for other cells
    - ? Promote motor neuron & DRG cell survival
    - ? via GDNF, or Neurotrophin 3 (NT3)
3. Immature Schwann cells
  - S100 antigen in cytoplasm
  - 04 antigen
  - Autocrine support of survival via
    - Neurotrophin 3 (NT3)
    - Insulin-like growth factor 2 (IGF2)
    - Platelet-derived growth factor BB (PDGF-BB)
  - Trophic support for other cells
    - Connective tissue development: Perineurium; Epineurium; Epineurium
    - 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"
4. Mature Schwann cells
  - Myelinating Schwann cell
    - 1st mature Schwann cell formed in development
    - Precursor
      - Promyelin Schwann cell
      - Forms association with one single axon
      - 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: Mild overexpression, or Knock out
      - ? Involvement of other myelin transcription factors
    - Express
      - Myelin proteins: P₀; Myelin basic protein; PMP-22
      - Cholesterol biosynthetic enzymes: HMG Co-A reductase; Oleoyl-Co-A synthase
    - Downregulated molecules
      - Neural cell-adhesion molecule (NCAM)
      - 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
  - Non-myelinating Schwann cell
    - Formed later than myelinating Schwann cells
    - Expressed molecules
      - Neural cell-adhesion molecule (NCAM),
      - Neurotrophin receptor, p75
      - Glial fibrillary acidic protein (GFAP)
    - Associated with several axons
Denervation: If mature Schwann cells lose contact with axons
- Wallerian degeneration
- Myelinating Schwann cells regress to cell type similar to immature Schwann cells

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 2⁵
  - 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 incisures
- Components: F-actin; Ezrin ; Radixin ; Moesin

Myelin Glycoproteins¹

Glycoprotein	Properties
P₀	Location: Compact PNS myelin 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 Structures⁶

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
Extracellular: Tenascin-C; Tenascin-R
Axon
- Membrane
  - Na⁺ channels
    - Voltage-gated
    - Types: Na_v1.6 > Na_v1.2, Na_v1.8, Na_v1.9
  - Neurofascin 186 splice variant
  - Nr-CAM
- Sub-membrane
  - Ankyrin_G : 480 & 270 kDa splice variants
  - Spectrin

Paranode

Anatomy
- Lateral edge of myelin sheath spirals around axon
- Axon & myelin sheath form axo-glial junctions
Paranodal Schwann cell membranes
- Connexin-32
- E-cadherin
- Myelin-associated glycoprotein
- Neurofascin 155 splice variant
Paranodal axon membrane
- General: Contains molecular components of septate-like junctions
- Contactin-associated glycoprotein (CASPR; CNTNAP1) : Heterodimer with contactin
- Neurofascin 186 splice variant
- Contactin
- NCP1 (Nieman-Pick, type C1 disease)
Axonal submembrane
- Band 4.1B
- F-Actin

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
    - K_vβ2
  - Caspr2
  - Tag1 (Contactin 2)
  - NCP2 (Nieman-Pick, type C2 disease)
- Axon submembrane proteins
  - PDZ domain of caspr2
  - Band 4.1B
  - F-Actin
Schwann cell membrane: K⁺ channels

Internodal region: Components

Axon
Compact myelin
Schwann cell cytoplasm & membranes
- Contains tripartite strand with components similar to juxta paranode
- Strand apposes inner mesaxon & inner region of Schmidt-Lantermann incisures
Basal lamina

Other myelin-related components

Peripheral myelin protein 2 (PMP2)
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
- PMP-22
Periaxin : CMT 4F (Dejerine-Sottas)
Myelin basic protein (MBP)
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
- Neurofascin 155 (NF155)
- TAG-1
- Gliomedin
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 & Denervated Schwann cell components

Glial fibrillary acidic protein (GFAP)
Growth associated protein 43 kDa (GAP-43)
F-spondin
Low affinity neurotrophin receptor/p75 (p75^NTR)
Neural cell adhesion molecule (NCAM)
L1 cell adhesion molecule (L1CAM)
- Disease: MASA; Spastic paraparesis
N-syndecan : Binds to novel collagen in extracellular matrix
N-cadherin :
Ninjurin
Amphiregulin
Myelin transcription factors
- PAX3
  - Disease: Waardenburg syndrome ± meningomyelocele
  - Interaction with SOX10
- c-jun
- Krox-24 (EGR1)
- Krox-20 (EGR-2)
  - Diseases: Congenital hypomyelinating neuropathy; CMT1
  - 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
    - 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
EGR-3
- Mouse knockout: Loss of spindles; Sensory ataxia

Myelin-associated glycoprotein (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 axonal regeneration in CNS: Binds to NOGO (NgR) with p75(NTR) coreceptor
MAG 2nd messenger: Fyn nonreceptor-type tyrosine kinase
Disease: Anti-MAG neuropathy

Return to Neuromuscular Home Page
Return to Demyelinating neuropathies

References
1. J. Molec Neurosci 1997;7:1-12, Cell Mol Life Sci 2002;59:1851�1871, J Neurol Sci 2005;228:187-189
2. Trends Neurosci 1999;22:402-410
3. Brain 2000;123:222-233
4. Glia 2000;29:154-165
5. Neuron 2001;30:677-687
6. J Periph Nerv Sys 2002;7:1-12

4/8/2006