Neuromuscular

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TROPHIC FACTORS 1

Agrin
Amphiregulin
Aria
Artemin
BDNF
Cardiotrophin-1
Ciliary neurotrophic factor  
c-kit
c-ret
CSF-1
EGF
FGFs: 1, 2, 5
FLT3L
GDNF
G-CSF
GM-CSF
Hedgehog
  Desert
  Sonic
Heregulin (Neuregulin)  
IGF 1, 2
Interleukin:
  2, 3, 4, 5, 6, 7,
  9, 11, 12, 13, 15
Leptin
LIF
Midkine
MuSK
Myostatin (GDF 8)
Netrins
Neurturin
NGF*
NT3
NT4/5
p75
Pleiotrophin
PDGF*
Persephin
Saposin C
Semaphorins
Stem cell factor
trk A; B; C
TGF: α; β
VEGF
Trophic factor classes
  Adhesion molecules
  Bone morphogenetic proteins
  Cytokines
  Eph receptor tyrosine kinase
  Epidermal growth factors
  Fibroblast growth factors
  GDNF
  Heparin-binding growth factors
  Insulin-like growth factors
  Neurotrophins
  Other
  Semaphorins
  Transforming growth factors β
  Tyrosine kinase receptor ligands
Related disease syndromes
  BDNF
  c-kit
  CNTF
  c-ret
  FGF receptors: 1, 2, 3
  GDNF
  Hedgehog
    Desert
    Sonic
  IGFs: 1; 2
  Neuregulin (ARIA)
  Neurotrophin-3
  Neurotrophin-4
  NGF receptor: p75R
  PDGF receptor β
  TGF: α; β-1
    β-Receptors
  trkA
  trkB
* Contains cysteine knot structure
See Somite lineages, Muscle & Bone


Neurotrophins
Binding of neurotrophins to receptors
  • All neurotrophins are capable of binding to p75 receptor
    • Pro-neurotrophins
      • Contain N-terminal fragment (~120 amino acids)
        • Cleaved to form mature neurotrophin
        • Cleavage mechanisms
          • Trans-Golgi: By furin
          • Secretory granules: By pro-protein convertases
      • Secreted extracellularly: Often at synapses
      • May preferentially bind to p75
      • ProNGF & proBDNF
        • Secreted by Schwann cels
        • May be cleaved by extracellular proteases
    • Binding of (pro)neurotrophins to p75
      • Produces activation of NFκB or c-jun N-terminal kinase activities
      • p75 may be located on presynaptic & postsynaptic membranes
      • Interaction of proNGF with p75NR induces apoptosis
  • Each neurotrophin also binds to a specific Trk receptor
    • Binding to Trk receptors is preferentially by mature neurotrophins
    • Binding to Trk receptors by neurotrophis activates different pathways than p75
      • Phosphatidylinositol 3-kinase (PI3K)
      • Mitogen-activated protein kinase (MAPK)
      • Phospholipase C-γ (PLC-γ)
    • Interaction of mature neurotrophins with Trk receptors usually enhances cell survival
Trophic factor Receptor PNS or muscle targets
Nerve growth factor (NGF) trkA
Low affinity NGFR (p75)
Sensory (small peptidergic)
Pain
Sympathetic
Brain-derived neurotrophic factor (BDNF) trkB
Low affinity NGFR (p75)
Sensory & Motor
Neurotrophin-3 (NT-3) trkC > trkA & trkB
Low affinity NGFR (p75)
Sensory (large) & Motor (γ)
Neurotrophin-4/5 (NT-4/5) trkB Sympathetic, Sensory & Motor
Neurotrophin-6 (NT-6): α β γ : Pseudogenes
External links: Murray-Rust; Developmental Biology


Cytokines 4
General features
  • Cytokines
    • Regulatory proteins secreted by white blood & other cells
    • More than 150 cloned
  • Structure: Most cytokines are simple polypeptides or glycoproteins with MW ≤ 30 kDa
  • Production of cytokines
    • Constitutive pproduction usually low or absent
    • Regulated by inducing stimuli at the level of transcription or translation
    • Transient
  • Action: Local
    • Autocrine: Bind to cell of origin
    • Paracrine: Bind to neighboring target cell
  • Receptors
    • Specific
    • High affinity
    • Cell surface
  • Endogenous inhibitors: Regulate cytokine activity
  • Classification
Trophic factor Receptors PNS or muscle targets Other
Neuropoietic cytokine common receptor subunits:
gp 130 (CD130) /LIFRβ +
Ciliary neurotrophic factor
  (CNTF)
CNTFRα Autonomic; Sensory;
Motor; Muscle
Cytokine receptor-like factor 1
  (CRLF1)
CNTFRα
Leukemia inhibitory
  factor (LIF)
LIFR Sympathetic; Sensory;
Motor
LIFRβ Knockout: Loss of
  preganglionic sympathetic neurons
Cardiotrophin-1 (CTF1) CT1R Motor; Muscle
Sympathetic neuroblast
CTF1 Knockout: Loss of
  preganglionic sympathetic neurons
Oncostatin-M OM1Rα/gp130
? OM1Rβ
Sympathetic neuroblast
Common receptor subunits: gp130/gp130 +
Interleukin-6 (IL-6) IL-6 receptor α
  (CD126)
Nerve differentiation;
Sympathetic; ? Muscle
Interleukin-11 (IL-11) IL-11 receptor α Sympathetic neuroblast
Common receptor subunit: γC (CD132) +
Interleukin-2 (IL-2) IL-2 receptor α
  (CD25)
IL-2 receptor β
Sympathetic neuroblast TH1 & NK cells
Proinflammatory
Interleukin-4 (IL-4) IL-4 receptor α
  (CD124)
IL-13 receptor α
Sympathetic neuroblast Promotes TH2
Activates B-cells
Regulatory
Interleukin-7 (IL-7) IL-7 receptor α
  (CD127)
CNS: Neuron progenitor
Interleukin-9 (IL-9) IL-9 receptor α CNS
  Neuron differentiation
Interleukin-15 (IL-15) IL-15 receptor α
IL-2 receptor β
CNS: Neuron progenitor
Common receptor subunit: βC (CDw131) +
Interleukin-3 (IL-3) IL-3 receptor α
  (CD123)
CNS: Neuron progenitor
Interleukin-5 (IL-5) IL-5 receptor α
  (CDw125)
CNS: Neuron progenitor
GM-CSF GM-CSF receptor α
  (CD116)
CNS: Neuron progenitor
Other receptor subunits
G-CSF G-CSF receptor
  (Dimer) (CD114)
CNS: Neuron progenitor
Leptin OB-Rb dimer
Interleukin 1 (IL-1) α
Interleukin 1 (IL-1) β
IL1 Receptor 1
IL1 Receptor 2
. Macrophages & T-cells
Proinflammatory
Interleukin 10 (IL-10) IL10 Receptor . Promotes TH2
IL-12
Regulatory
Interleukin 12 (IL-12) IL12 Receptor β1
IL12 Receptor β2
CNS: Neuron progenitor TH1 & NK cells
Proinflammatory
Interleukin 13 (IL-13) IL13 Receptor α

Hemopoietin receptors
  • Multiple receptor subunits
  • No intrinsic tyrosine kinase activity
  • Cytoplasmic receptor microdomains organized
    • Bind transposable cytoplasmic effector proteins
      • Janus: JAK-1 ; TYK2
      • src tyrosine kinases
      • lipid & serine-threonine kinases
    • Docking sites for SH2-containing molecules: STAT
    • Integrate diverse effector pathways


Insulin-like growth factors
Trophic factor Receptor PNS or muscle targets
Insulin-like growth factor 1 (IGF1) Type 1 IGF receptor (IGFR-1) >
Insulin receptor (IR)
Sympathetic, Sensory & Motor
Muscle
Insulin-like growth factor 2 (IGF2) IGFR-1 > IR
IGFR-2
Sympathetic, Sensory & Motor
Muscle


Transforming growth factors β (TGF-β)
Trophic factor Receptor PNS or muscle targets
GDNF family
Artemin c-ret (signaling)
GFR-α3 (binding)
Superior cervical ganglion
Peripheral nerve
Dopamine neurons
Glial-derived neurotrophic factor
  (GDNF)
c-ret (signaling)
GDNF Family Receptor α1
    (GRFRα1) (binding)
Autonomic, Enteric,
Sensory & Motor
Neurturin c-ret (signaling)
GFR-α2 (binding)
Sympathetic; Sensory
Motor
Persephin c-ret (signaling)
GFR-α4 (binding)
Motor; Dopaminergic
TGFβ family
Bone morphogenetic proteins..
Sonic Hedgehog fly Patched fly
Smoothened fly
Myostatin (GDF 8) Activin type II receptor B Muscle: Growth inhibition
Transforming growth factors β
1 , 2* , & 3
TGF-β receptors type I , II & III
(Serine-threonine receptors)
Sensory & Motor
Muscle: Biglycan


Fibroblast growth factors (FGF)
Trophic factor Receptor PNS or muscle targets
Fibroblast growth factor 1
  (acidic)
FGF receptors
  1 , 2 , 3 & 4
Autonomic, Sensory & Motor
FGF 2 (basic) FGF receptors 1 - 3 Autonomic, Sensory & Motor
FGF 5 FGF receptors 1 & 2 Motor


Epidermal growth factors
Trophic factor Receptor PNS or muscle targets
Amphiregulin Epidermal growth factor receptor Schwann cells
Neuregulin (ARIA)
NEU/ERBB2 & 3 receptor
  tyrosine kinase
Muscle
  AChRs increase
Peripheral nerve
Transforming growth factor α
  (TGF-α)
Epidermal growth factor receptor Sensory
Neuregulin 2 EGF receptors 1 , 2 , 3 , 4
Neuregulin 3 ERBB4 receptor tyrosine kinase Brain; Ganglia

Netrins 7
Trophic factor Receptors PNS or muscle targets
Netrin 1 UNC5A
UNC5B
UNC5C
UNC5D
DSCAM
Neogenin
DCC
Chemo-repellant
Axonal growth cones
Oligodendrocyte differentiation
Netrin 3 (Netrin 2-like) Chemo-repellant
Netrin 4  
Netrin G1 LRRC4C (NGL-1) Axon guidance
Netrin G2 LRRC4 (NGL-2) Axon growth


Heparin-Binding Growth Factors
Trophic factor Receptor PNS or muscle targets
Pleiotrophin (NEGF1) Syndecan-1 Muscle (NMJ)
Midkine (NEGF2) Syndecan-1 Muscle
Neurite outgrowth
Vascular endothelial growth factor
  (VEGF) *
VEGFR1/Flt-1 & VEGFR2/Kdr
Heparan sulfate & Heparin
Neuropilin-1 : VEGF 165
Vascular endothelium
Blood-Brain barrier


Tyrosine kinase receptor ligands
Trophic factor Receptor PNS or muscle targets
Stem cell factor c-kit Sensory
Neural crest
Agrin Receptor tyrosine kinase MuSK Muscle
  AChRs localize
FLT3L flt3 (CD135)
Macrophage colony
stimulating factor-1 (CSF-1)
c-fms
Platelet derived growth factor (PDGF)
Isoforms AA , AB, BB
PDGF α & β receptors Motor
Vascular endothelial growth factor
  (VEGF) *
VEGFR1/Flt-1 & VEGFR2/Kdr
Heparan sulfate & Heparin
Neuropilin-1 : VEGF 165
Vascular endothelium
Blood-Brain barrier
Vascular endothelial growth factor-B
  (VEGF-B)
Heparin
Neuropilin-1
Heart
Muscle
Vascular endothelial growth factor-C
  (VEGF-C)
Flt-4
Muscle
Vascular endothelial growth factor-D
  (VEGF-D)
VEGFR2/Kdr
VEGFR3/Flt-4
Muscle


Other
Trophic factor Receptor PNS or muscle targets
Saposin C G-protein mediated Peripheral nerve regeneration
Myelination
Semaphorins Axonal growth cones





TROPHIC FACTOR RELATED DISORDERS

Brain-derived neurotrophic factor (BDNF) c-kit
  Chromosome 4q12 Ciliary neurotrophic factor (CNTF) : Ciliary neurotrophic factor receptor (CNTFR): Related disorders c-ret
  Chromosome 10q11.21 Fibroblast growth factor receptor 1 5
  Chromosome 8p11.23-p11.22 Fibroblast growth factor receptor 2
  Chromosome 10q26.13 Fibroblast growth factor receptor 3
  Chromosome 4p16.3
Glial-derived neurotrophic factor (GDNF) Sonic Hedgehog
  Recessive; Chromosome 7q36.3 Insulin-like Growth Factor 1
  Recessive; Chromosome 12q23.2 Insulin-like Growth Factor 2 NGF p75 receptor Myostatin Neuregulin (ARIA; NRG1) Neurotrophin-3
  Chromosome 12p13.31 Neurotrophin-4 (NT4)
  Chromosome 19q13.33 Patched
  Chromosome 9q22.32 Platelet-derived growth factor receptor β
  Chromosome 5q32 Transforming growth factor-α Transforming growth factor-β 1 Transforming growth factor-β Receptors: 1 (TGFBR1) & 2 (TGFBR2) trkA trkB VEGF

Fibroblast Growth Factors



Bone morphogenetic proteins 2




Semaphorins 3



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References
1. Ann Neurol 1996;40:346-354
2. Trends Neurosci. 1997;20:309-317
3. Trends Cell Biol 1996; 6:15-23
4. Trends Neurosci 1997;20:357-365, Muscle Nerve 2003;28:659Ė682
5. Human Mutation 1999;14:115-125
6. Am J Hum Genet 2003; Online July
7. Development 2011;138:2153-2169

10/23/2014