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TROPHIC FACTORS ¹

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	Patched Smoothened
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 Factors: Related Disorders

• Secreted
  • Mechanism: Activity & Ca⁺⁺ dependent
  • May control synaptic transmission & long-term synaptic plasticity
  • ? Related to local & synapse-specific modulation
• Variant allele in Pro- region: Val66Met ⁶
  • Protective effect in Obsessive-Compulsive disorder & other psychiatric disorders
  • High frequency in Alzheimer’s, Parkinson’s, & bipolar disorders
  • Associated with impaired hippocampal activity & episodic memory function
• Mouse knockout
  • Sensory ganglion cells
    • Slowly-adapting mechanoreceptors: Less sensitive
    • Reduction in number of cells in trigeminal & vestibular ganglia
    • Worse defect when NT4 also deficient
  • Normal sympathetic & motor neurons

• Piebaldism : Congenital patches of white skin & hair lacking melanocytes

• Neuropoetic cytokine family: Share amphipathic helical domain
• Humans
  • Homozygosity for defects in CNTF (No CNTF production): No disease
• Mouse knockout
  • Postnatal weeks: No functional or morphological changes progressive
  • Increasing age: Atrophy and loss of motor neurons
  • External link: Jackson

• Cold Sweating syndromes
  • CISS1 (Crisponi syndrome): Cytokine Receptor-Like Factor 1 (CRLF1)
  • CISS2
  : Cardiotrophin-like cytokine factor 1 (CLCF1)
• Stuve-Wiedemann syndrome: Leukemia Inhibitory Factor Receptor (LIFR)

• Multiple endocrine neoplasia: Types 2A and 2B
• Hirschsprung's disease
• Medullary thyroid carcinoma
• Recombination of c-ret C-terminal with other genes produces oncogenic protein

• Pfeiffer syndrome
  • Skull: Craniosynostosis
  • Digits
    • Thumbs & Great toes: Enlarged & deviated
    • Phalangeal ankylosis
    • Syndactyly: Soft tissue
• Osteoglophonic dysplasia
• Hypogonadotropic Hypogonadism ± Anosmia 2 (HH2)
• Kallman syndrome 2
• Encephalocraniocutaneous lipomatosis, somatic mosaic
• Hartsfeld syndrome
• Jackson-Weiss syndrome
• Trigonocephaly 1
• External link: Zygote

• Pfeiffer syndrome
• Crouzon syndrome: Craniofacial dysostosis
  • Skull: Craniosynostosis; Hypertelorism
  • Eyes: Exophthalmos; External strabismus
  • Face: Parrot beaked nose; Short upper lip; Small maxilla
• Jackson-Weiss syndrome
  • Craniofacial abnormalities
  • Feet
    • Broad great toes with medial deviation
    • Tarsal- metatarsal coalescence
• Apert syndrome
  • Craniosynostosis
  • Syndactyly: Cutaneous & bony
• Beare-Stevenson cutis gyrata syndrome
• Saethre-Chotzen syndrome
• Antley-Bixler
• Bent bone dysplasia syndrome
• Craniofacial-skeletal-dermatologic dysplasia
• Gastric cancer, somatic
• LADD syndrome 1
• Scaphocephaly & Axenfeld-Rieger anomaly
• Alleles associated with risk of sporadic postmenopausal breast cancer

• FGFR3 protein
  • Types
    • Cell-surface receptor
    • Secreted form
    • Absent extracellular domain on some isoforms
  • Domains
    • Extracellular
      • 2 or 3 immunoglobulin (Ig)-like domains
    • Transmembrane
    • Cytoplasmic: Tyrosine kinase
  • Binding partner: Botulinum toxin A
  • Functions
    • Required for normal skeleton & inner ear development
    • Regulates osteogenesis & postnatal bone mineralization by osteoblasts
    • Regulation of chondrocyte differentiation, proliferation & apoptosis
• IgG vs FGFR3: Sensory neuronopathy/neuropathy
• Hereditary disorders
  • Genetic disease mechanisms
    • Some mutations lead to constitutive (ligand independent) activation of FGFR3
  • Achondroplasia
    • Short-limbed dwarfism
    • Head: Large; Frontal bossing; Mid-face hypoplasia
    • Hands: Trident configuration
    • Spinal stenosis
  • Crouzon syndrome
  • Distal arthrogryposis 6 (DA6)
  • Thanatophoric dysplasia
    • Neonatal; Lethal
    • Head: Large; ± Cloverleaf skull
    • Limbs: Severe shortening; ± Curved femur
    • Trunk: Narrow thorax; Short ribs
  • Hypochondroplasia : Short stature; Micromelia; Lumbar lourdosis
  • Skeleton-Skin-Brain Syndrome: Lys650Met
    • Neural
      • Developmental delay
      • Corpus callosum: Hypoplastic
      • Cerebellum: Abnormal development
    • Short stature: Achondroplasia
    • Acanthosis nigricans
  • Camptodactyly, tall stature & hearing loss (CATSHL) syndrome
  • Saethre-Chotzen-like syndrome
  • Muenke syndrome
    • Coronal synostosis: Pro250Arg mutation
  • HMSN: 4p microdeletion

• Mechanisms: Signal via a multicomponent receptor system
  • α component (Ligand binding subunit): Glycosyl-phosphatidylinositol (GPI)-linked
  • β component (Signaling): receptor tyrosine kinase (RET)
  • Neurturin acts by similar mechanisms
• Hirschsprung's megacolon
• GDNF disorders: Animal models
  • GDNF overexpression by muscle
    • Increased number of motor axons innervating NMJs
  • Mouse knockout: GDNF
    • Renal agenesis: Due to lack of induction of ureteric bud
    • Absent enteric neurons
      • Pyloric stenosis
      • Duodenum dilation
  • Mouse knockout: GDNF family receptor α 3 (GFRA3)
    
    • Defects in superior cervical ganglion

• Disease: Holoprosencephaly, Type 3
• Overexpression: Basal cell nevus syndrome
• ? Oncogene
• See: Sonic hedgehog & Myogenesis
• Also see: Desert hedgehog
• External links
  • Hedgehog proteins
  • Hedgehog database

• IGF-I Functions
  • Nerve: Promotes nerve elongation & branching
  • Muscle: Promotes cell proliferation, differentiation & hypertrophy
  • Increases activity of epithelial sodium channel
• Diseases
  • IGF-1 deficiency
      ● Recessive; Chromosome 12q23.2
    • Genetic
      • Mutations: Exon deletions, Missense, Polyadenylation signal
    • Clinical
      • Growth retardation: Prenatal & postnatal
      • Microcephaly
      • Single palmar creases
      • Deafness: Sensorineural
      • Mental retardation
      • Lab: Excess growth hormone secretion; Insulin resistance
  • Acromegaly: Increased levels
• Knockout mice
  • IGF-I
    • Low body weight (< 60% of normal)
    • Muscle: Underdevelopment
    • Lung: Poorly defined alveoli
    • Lifespan: Perinatal death
  • IGF-I R
    • Low body weight (< 45% of normal)
    • Organ hypoplasia
    • Lifespan: Perinatal death

• Knockout mice
  • Transmission through male germline
    • Heterozygotes: Growth-deficient
    • Homozygotes: Growth-deficient
  • Transmission through female germline
    • Heterozygotes: Phenotypically normal
    • Homozygotes: Growth-deficient
• Muscle
  • Normal adult muscle: Monoallelic expression of IGF2
  • Muscle fiber differentiation: IGF-2 gene increased
  • Rhabdomyosarcoma
    • 2 or more copies of active IGF2 alleles
    • Arise by relaxation of imprinting or duplication of the active allele
    • ? IGF-2 increase: Promotes initiation or progression of rhabdomyosarcoma
• IGF-2 overexpression in mice: Beckwith-Wiedemann like syndrome
• Overexpressed in Wilm's tumor
• IGF-2 Receptor
  • Also mannose 6-phosphate receptor
  • Functions: Often growth inhibition
    • Trafficking of lysosomal enzymes
    • Activation of TGFβ, a potent growth inhibitor
    • Degradation of IGF2
  • Hepatocellular carcinoma: Mutations & Reduced function

• Knockout mice
  • Sensory: Reduced (50%) numbers of most types of sensory axons
  • Sympathetic: Normal
  • Cutaneous sensory trigeminal neurons: Require more NGF for survival
• External link: Molecular diagram

• Member of TGFβ superfamily
• Structure: Homodimer
• Negative regulator of skeletal muscle growth
• Inactivation: Increase in muscle mass due to hyperplasia & hypertrophy
• Animal disease: Double-muscled cows
• High levels: HIV infection with muscle wasting
• Knockout mice
  • Muscles twice normal size
  • Increases myoblast division & muscle fiber size

• Receptors: NEU/ERBB2 & 3 receptors
• Molecular family: Epidermal growth factors
• Gene: Encodes 30 different isoforms
• Functions
  • Muscle: Regulates AChR synthesis at NMJs
    • Signalling pathway at NMJ: Cdk5 kinase
    • Increases synthesis of acetylcholine receptors
    • Increases epsilon-subunit mRNA levels up to 10-fold
    • Responsible for switch from gamma subunits to epsilon subunits
  • Nerve
    • Schwann cells
      • Stimulates proliferation, migration & survival ± myelination
      • Suppresses Mitf stimulated development of "repair" Schwann cells
    • Developing nerves: NRG1 on axon membrane activates ErbB2-ErbB3 receptor tyrosine kinase on associated glia
    • Type III isoform mutants
      • Over expression: Thick myelin
      • Reduced expression: Schwann cells or myelin reduced
  • Oligodendroglia
    • Supports survival of purified oligodendrocytes & aged oligodendrocyte precursors
• Disorder: Motor-Sensory Neuropathy, Recessive
• Knockout mice
  • Die at embryonic day 10.5 from cardiac defects
  • Nerve
    • Normal trajectory & outgrowth, but that the projections
    • Structure: Defasciculated; Abnormal branching
    • Schwann cells: Generated but fail to survive
  • Neuromuscular junctions: Abnormal development
  • Muscle: Immature

• Neuromuscular junction
  • Regulates neurotransmitter release at neuromuscular synapses
  • Action requires TrkC
  • Mediators: Simultaneous activation of PI3K and PLC-γ/IP3 signaling pathways
  • Loss of NT3: Causes defective synaptic vesicle recycling
• General roles
  • Neuronal survival & differentiation
  • Levels: High during fetal development
• Locations
  • Dorsal root, Nodose, Sympathetic ganglia
  • Motor neurons
  • Trigeminal mesencephalic nucleus
  • Other CNS: Hippocampus, Cerebellum, Dopaminergic & GABAergic cells in ventral mesencephalon
  • Adult: Hippocampal dentate gyrus
• Receptors
  • TrkC
  • p75^NTR
  • A9β1 integrin
• Homozygous knockout mice
  • Sensory ataxia & Choreoathetosis
  • Pathology
    • Loss of large sensory ganglion cells
    • Absent muscle spindles & Golgi tendon organs
    • Cardiac: Abnormal development of atria, ventricles & cardiac outflow tracts
• Overexpression
  • Increased number of spindles in muscle
  • Increased spindles in muscle: Other disorders

• Activates: Receptor TrkB by triggering phosphorylation
• General roles
  • Neuronal survival & differentiation
• Locations
  • Trigeminal, Dorsal root, Jugular, Sympathetic, Nodose ganglion
  • Hippocampus, Dopaminergic & GABAergic neurons (Ventral mesencephalon), Medulla, Hypothalamus, Thalamus, Cerebellum
• Receptors
  • TrkB: High affinity
  • p75^NTR
• Disease: Primary Open-Angle Glaucoma
  • Inheritance: Dominant
  • Mutations: Heterozygous; Missense
• Mouse knockout
  • Loss of Aδ D-hair receptor fibers

• Receptor for Hedgehog proteins
• Basal cell nevus syndrome

• Chronic myelomonocytic leukemia
  • Chromosomal translocation with ETS-like protein TEL
• Muscle satellite cells: Stimulates proliferation & inhibits differentiation

• Knockout mice
  • Aberrant whiskers, fur and hair follicles
  • Eye abnormalities

• Disease: Camurati-Engelmann disease
• Knockout mice
  • Death: 20 days after birth due to wasting syndrome
  • Multifocal, mixed inflammatory cell response and tissue necrosis
  • Elevated levels of class I and class II MHC
• Influences extracellular matrix organization
  • Stimulates reconstruction of basement membranes

Transforming growth factor-β Receptors: 1 (TGFBR1) & 2 (TGFBR2)

• Loeys-Dietz syndrome, type 1 / 2
  • Clinical systems: Disordered development
    • Cardiovascular
    • Craniofacial
    • Neurocognitive
    • Skeletal
  • Pathology: Increased expression of
    • Collagen & connective tissue growth factor
    • Nuclear enrichment of phosphorylated Smad2

• Congential sensory neuropathy with anhidrosis (HSAN 4)

• Mouse knockout
  • Vestibular dysfunction
    • Reduction in number of cells in vestibular ganglia
  • Death in 1st post-natal weeks
    • Failure to develop normal respiratory patterns

• May facilitate glucose passage across the blood-brain barrier
• Disorders
  • Increased serum levels in
    • POEMS syndrome
    • Scleroderma
  • Susceptibility to: Atherosclerosis; Alzheimer's; NIDDM-related retinopathy; ALS

Fibroblast Growth Factors

• Family of many related 150 to 268 amino acid proteins
• Control normal growth and differentiation of
  • Mesenchymal, epithelial & neuroectodermal cells
• Several groups: Basic & acidic originally isolated from brain tissue
  • Basic
    • FGF-2
    • Identified by proliferation-enhancing activities on murine fibroblasts (3T3 cells).
  • Acidic
    • FGF-1
    • Identified by proliferation-enhancing activity for myoblasts.
    • Others: int-2 (FGF-3); FGF-5; FGF-6; K-FGF; Keratinocyte growth factor (FGF-7)
• Other properties
  • Variably secreted
    • Secreted: FGF-3, 4, 5, 6, 7, 8
    • Not secreted: FGF-1; FGF-2; FGF-9; FHFs
  • Heparin binding of FGFs is strong
  • Skeletal muscle location: FGF-5 & FGF-6
• Some FGFs are oncogenes
  • 3 : Deafness, congenital with inner ear agenesis, microtia & microdontia
  • 4
  • 5 : Trichomegaly
  • 6
  • 7
  • 8
    • Required for limb outgrowth
    • Kallman syndrome 6 (Hypogonadotropic hypogonadism 6 ± Anosmia (HH6))
  • 9
    • Absence: Male-to-Female sex reversal & Lung hypoplasia
    • Multiple synostoses syndrome 3
• Other FGFs
  • FGF Homologous Factors (FHF)
    • FGFs
      • 1 (FGF 12) : Developmental & Epileptic Encephalopathy-47 (DEE47)
      • 2 (FGF 13) : Developmental & Epileptic Encephalopathy-90 (DEE90)
      • 3 (FGF 11)
      • 4 (FGF 14) : SCA27
    • General properties
      • Expressed primarily in the nervous system
      • Contain clusters of basic residues that can act as nuclear localization signals
      • Lack a classic signal sequence: Probably not secreted
  • FGF 7 : Presynaptic organizing molecule in brain
  • FGF 10
    • FGFR2b ligand
    • Aplasia of salivary & lacrimal glands, Autosomal dominant
    • Presynaptic organizing molecule in brain
  • FGF 16 ; 17
  • FGF 18 : Positive effect in osteogenesis; Negative effect in chondrogenesis
  • FGF 19 : Inner ear development
  • FGF 20
    • Location: Dopaminergic neurons of SN; Cerebellum
    • Parkinson's disease : Increased risk with FGF 20 polymorphisms
    • Binds to FGF receptor FGFR-1c
  • FGF 21
    • Serum levels high in: Mitochondrial disorders
  • FGF 22 : Hair development; Presynaptic organizing molecule in brain
  • FGF 23
    • Hypophosphatemic rickets, Autosomal dominant
    • Familial tumoral calcinosis with hyperphosphatemia
• FGF receptors (FGFRs)
  • 4 types of high affinity receptors
    • Tyrosine kinases
    • FGFR-1 & FGFR-4 expressed in regenerating muscle
  • Low affinity receptors: Heparan sulfate proteoglycans
    • FGFR-2: Syndecan
  • FGFR3
    • Autoantibodies
    • Syndromes
  • Fibroblast growth factor receptor-like molecule 1 (FGFRL1)
    • Homologus to other FGFRs but lacks cytoplasmic domain
    • Expression: Cartilage; Fetal muscle (weak)

Bone Morphogenetic Proteins ²

• Transforming growth factor-β family
• Classes
  • Decapentaplegic protein (Dpp) ; BMP2 ; BMP4
  • 60A ; BMP5 ; BMP6 ; BMP7/OP1 ; BMP8a/OP2 ; BMP8b/OP3
  • BMP3 (Osteogenin) ; GDF10
  • BMP9; BMP10; Dorsalin-1
  • BMP12/GDF7 ; BMP13/GDF6 ; GDF5
  • GDF3/Vgr2
  • Vg1 ; Univin
  • BMP14; BMP15; GDF1 ; Screw ; Nodal ; XNrI-3; Radar; Admp
• Mediate developmental processes: Stage-specific effects
  • Cell survival
  • Death (Apoptosis): Rhombencephalic neural crest cells by BMP4
  • Muscle
    • BMP2: Stimulates conversion to bone pathway
    • BMP7: Induces muscle cell proliferation
  • Morphogenesis
    • Act as gradients: Dpp, BMP2, BMP4
    • Promote differentiation of dorsal & intermediate cell types
    • Antagonistic to ventral cell types (Promoted by Sonic hedgehog )
  • Local cell-cell communications
  • Lineage commitment; Inhibition of alternate lineages
    • Ectoderm
      • Initially inhibit ectoderm formation during gastrulation
        
      • BMP4 inhibition required for conversion of ectoderm to neuroectoderm
    • PNS
      • Instructive signals for neuronal lineage commitment: BMP2 or BMP4
        
      • Promote graded stages of neuronal differentiation
    • CNS
      • Promote astroglia from subventricular zone: Synergistic with gp130
        
      • Suppress neuronal & oligodendroglial lineages
        
      • Promote survival & differentialtion of specific neurons & cells
  • Cell differentiation
  • Left-right differentiation: Nodal
• Receptors: Transduce intracellular signals through serine-threonine kinase subunits
  
  

  	BMP binding proteins
  BMP ligand	Type-I receptor	Type-II receptor	Other
  Dpp	Thick veins Saxophone DAFI	Punt DAF4
  BMP2 BMP4	BMPRIA BMPRIB	BMPRII	Noggin Chordin
  BMP7	BMPRIB ActRI	BMPRII ActRII ActRIIB	Follistatin
  GDF5	BMPRIB	BMPRII ActRII
  Activin			Follistatin

Semaphorins ³

• Protein properties
  • Gene family containing both transmembrane & secreted proteins
  • ~750 amino acids
  • Domains
    • N-terminal signal peptide
    • ~500 amino acid sema domain: Conserved regions
      • ~15 cysteine residues
        
      • N-linked glycosylation sites
    • Ig (C2) domain: On secreted ± transmembrane proteins
    • C-terminal region
      • Secreted semaphorins: contain region of basic amino acids
        
      • Transmembrane domain in transmembrane proteins
• Protein types
  • Transmembrane semaphorins
    • Sema I (fasciclin IV) (G, D & T forms)
      • Peripheral axon guidance cue
    • D-sema II
      • Selective inhibitor of synaptic arborizations
    • Sem B
    • Sem C
  • Secreted semaphorins
    • Semaphorin III/F (Collapsin I; D/M-Sema-III)
      • Contact dependent collapse of sensory growth cones
        
      • Probably steers away sensory growth cones in vivo
        
      • Acts through, pertussus-sensitive, G-protein coupled cascade
        
      • Also via CRMP-62 mediator protein
    • Semaphorin A-V (Mouse Sema A)
      • Non-neural
        
      • Expression altered in small cell lung cancers
    • Semaphorin IV : 50% homology to mouse Sema E
    • Coll-2
    • CD-100
      • Leukocyte activation antigen
        
      • ? Guides spinal commissural interneurons & retinal afferents
  • ? type: Col 3,4 & 5
• Other repulsive growth cone guidance cues
  • Surface membrane: Connectin , MAG
  • Diffusible: Netrin 1 & 2
  • Extracellular matrix: Tenascin ; Janusin; Proteoglycans; Eph receptor tyrosine kinase ligands

Myokines: Muscle Secretome ⁸

Definition

• Endogenous hormone-like factors released from skeletal muscle

Satellite Cells & Myoblasts: Proliferation & Differentiation

• IL-6 Activates a cell surface signaling assembly with IL6RA (IL6R) & gp130
• IL-7
• LIF
• TGF-β
• IGF-1
• Myostatin
• Osteoglycin (OGN): Myoblast proliferation
• Follistatin-like 1 (FSTL1): Myoblast proliferation
• Ciapin1: Myotube differentiation

Myofibers: Substrate oxidation; Hypertrophy

• Myostatin
• Decorin
• IGF-1
• TGF-β
• Apelin
• IL-15
• Il-6

Fibroblasts: Extracellular Matrix

• TGF-β
• CTGF

Extracellular Matrix: Production; Organization

• FSTL1
• SPARC
• Cathepsins
• MMPs

Endothelial cells: Proliferation; Migration

• Cyr61
• IL-8
• VEGF

Immune cells: Recruitment; Activation

• IL-10
• Fractalkine
• CC-chemokine ligand 2 (CCL2)
• TNF-α
• IL17A

Other

• Peroxiredoxin 1
• Insulin-like growth factor binding protein 5
• Annexin A2
• Cofilin 1, nonmuscle
• Profilin 1
• Glyceraldehyde-3-phosphate dehydrogenase
• Secreted acidic cysteine rich glycoprotein
• NAC α domain containing
• Fibulin-2 precursor
• Eukaryotic translation elongation factor 1 β2
• Chloride intracellular channel 4
• Phosphatidylethanolamine binding protein 1
• Hypoxanthine-guanine phosphoribosyltransferase
• Malate dehydrogenase 1, NAD (soluble), isoform CRA_c
• Histidine triad nucleotide binding protein 1
• Peroxiredoxin 2
• Small nuclear ribonucleoprotein polypeptide D2
• Lactate dehydrogenase A
• Proteasome subunit β type-5 precursor
• AP-1, β 1 subunit, isoform CRA_a
• Cu/Zn superoxide dismutase
• Sterile α motif domaincontaining protein 3
• Transgelin 2
• Ubiquitin-activating enzyme E1-like 2, isoform CRA_b
• Proteasome subunit β type-4
• Serine (or cysteine) proteinase inhibitor, clade C, member 1
• α-1(XVIII) collagen
• β-tropomyosin
• Rho GDP dissociation inhibitor (GDI) α
• Aldo-keto reductase family 1, member A4
• Annexin A1