Cover 1
Half-title 3
Title 5
Copyright 6
Dedication 7
Contents 9
Preface 11
Contributors 13
1 Introduction to the Schwann cell 17
Theodor schwann 1810-1882 17
The schwann cell \u2013 more than meets the eye 18
Myelinating Schwann cells 20
Non-myelin-forming Schwann cells 22
Satellite cells 23
Schwann cells of the neuromuscular junction \u2013 the perisynaptic Schwann cells 24
Schwann cells respond to injury 25
Schwann cells orchestrate inflammation in the peripheral nervous system 26
Schwann cells and diseases of the peripheral nervous system 27
The 'schwann song' for the neuronocentric nervous system 28
2 Early events in Schwann cell development 29
Introduction 29
The initial development of peripheral nerves 29
Outline of the schwann cell lineage 30
Molecular profile, signalling responses and tissue relationships define each stage of the lineage 36
Molecules that control gliogenesis from the neural crest 36
Sox-10 41
Notch 41
BMP2 and 4 42
NRG1 42
The generation of immature schwann cells 44
Functions of schwann cell precursors and their derivatives 47
Events just prior to myelination 49
Radial sorting 49
Control of schwann cell numbers: proliferation and death 50
Myelination brakes 50
Signals that promote myelination 51
3 The molecular organisation of myelinating Schwann cells 53
Introduction 53
Reciprocal relationships form myelinated axons 54
Myelin lamellae 55
Junctional specialisations 57
Specialisations at nodes of ranvier 60
Specialisations at paranodes 64
Specialisations at juxtaparanodes 65
The internodal region 83
Demyelination alters the molecular architecture of axons 85
Conclusion 85
4 The role of the extracellular matrix in Schwann cell development and myelination 87
Introduction 87
Extracellular matrix in endoneurium 87
Collagens 88
Proteoglycans 89
Tenascin 90
Vitronectin 91
Fibronectin 91
Fibrinogen and fibrin 92
Basal lamina and schwann cell myelination 92
Laminins and laminin receptors 93
Multiple laminins in schwann cells 94
Multiple laminin receptors in schwann cells 95
Laminin receptor expression in schwann cell development 98
Multiple roles for laminin and laminin receptor pairs in schwann cells (see also table 4.2) 100
Radial sorting 100
Postnatal abnormalities in the morphogenesis of the myelinated axon and nodes of Ranvier 102
Conclusions 103
5 The biology of perisynaptic (terminal) Schwann cells 104
The tripartite organisation of the neuromuscular junction (NMJ) 105
Brief history of perisynaptic schwann cells 108
Are perisynaptic cells at the NMJ of schwann cell origin? 111
Roles of PSCs in synaptogenesis 112
Are Schwann cells necessary for axon outgrowth to target muscles? 112
Are PSCs necessary for the development of NMJs? 112
Roles of schwann-cell-derived factors in synaptogenesis 117
Roles of PSCs in synaptic transmission 118
Can PSCs 'listen' to nerve terminals? 118
Can PSCs 'talk' to nerve terminals? 119
Roles of PSCs in the maintenance of the adult NMJ 120
Roles of PSCs in remodelling and regeneration 123
Remodelling 123
Regeneration 125
Conclusions 131
6 Cytokine and chemokine interactions with Schwann cells: the neuroimmunology of Schwann cells 132
Introduction 132
Cytokines and chemokines 133
Cytokines and schwann cells in diseases of the PNS 134
Demyelination, inhibition of melin synthesis, myelination and remyelination 139
Schwann cell differentiation and dedifferentiation 140
Cytokines, schwann cells and PNS regeneration 141
In vitro studies of cytokine and schwann cell interactions 141
Effect of major histocompatibility molecules expression 141
Effect on expression of adhesion molecules 142
Effect on Schwann cell proliferation 143
Schwann cell synthesis of cytokines 144
Effect on Schwann cell viability 145
Effect on Schwann cell development and maturation 146
Chemokines and schwann cells in diseases of the PNS 148
Conclusion 149
7 Schwann cells as immunomodulatory cells 150
Introduction 150
Setting the stage: immune-mediated inflammatory disorders of the PNS 151
Antigen recognition by schwann cells 152
Schwann cells as antigen-presenting cells 153
Schwann cells as regulators of an immune response 155
Schwann cells as terminators of the immune response 156
Schwann cells as immunocompetent cells 156
8 Mutations in Schwann cell genes causing inherited neuropathies 158
Introduction 158
Biological background 159
Peripheral myelin protein-22 KD 163
PMP22 mutations causing CMT1A and HNPP demonstrate the importance of gene dosage for normal myelination 163
PMP22 and axonal degeneration 166
Skin biopsies to evaluate PMP22 levels in CMT1A and HNPP 167
Myelin protein zero (MPZ) 168
MPZ and CMT1B 168
MPZ mutations that disrupt protein structure or truncate the cytoplasmic domain are associated with early onset phenotype 172
Dominant negative and gain of function models for early-onset CMT1B 174
H10P causes a 'dying back gliopathy' and accumulation of proteinaceous material within the intralaminar space but not demyelination 176
Connexin 32 (Cx32) 177
CMT is caused by mutation in the gene encoding Cx32, a gap junction protein localised to the paranodal region and incisures of the myelinating Schwann cell 177
How might mutations in GJB1 cause CMTX? 179
Do most CMTX1 patients have loss of function phenotypes? 180
Transient CNS abnormalities in CMTX1 181
CMT1 is caused by mutation in the gene encoding EGR-2, a transcriptional regulator of myelin gene expression 182
LITAF/SIMPLE mutations cause CMT1C 183
CMT4F is caused by mutation in the gene encoding periaxin, a protein involved in Schwann cell\u2013basal lamina interactions 184
CMT4B 1 and 2 are caused by mutations in genes encoding myotubularin-related phosphatases 185
CMT4A is caused by mutation in the gene encoding the ganglioside-induced-differentiation-associated-protein-1 (GDAP1) 187
SOX10 and PLP1 mutations cause disease in schwann cells and oligodendrocytes 187
Sox10 mutations 187
PLP1 mutations 188
9 Guillain-Barre syndrome and the Schwann cell 190
The definition and then subdivision of Guillain-Barre syndrome 190
Pathology of GBS 191
Acute inflammatory demyelinating polyradiculoneuropathy 191
Axonal forms of GBS 195
Fisher syndrome and experimental models 196
Natural history 196
Treatment 197
Pathogenesis 198
Antecedent events 198
Molecular mimicry 199
Fisher syndrome 199
Immune responses in AIDP 201
10 Chronic idiopathic demyelinating polyneuropathy and Schwann cells 203
Clinical features 204
Pathology 205
Immunopathology 206
Immunogenetics 206
Cellular immune mechanisms 208
Cellular and immune responses 210
Humoral responses 212
Treatment 215
References 217
Index 279