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The Guidance of Axons
to Their Targets
서울대학교 어린이병원 신경외과
왕 규 창
Axon Growth: Two Views
molecular view random growth with selective survival
stereotropism• mechanical guidance• along scratches, blood vessels or cartilage
resonance• congruent activity
Retina-Tectum Experiment
Roger Sperry, 1940s lower vertebrates regeneration of cut retinal axons frog, cut optic nerve, rotation of
the eye
Retina-Tectum Experiment chemical matching rather than functional valid
ation of random connection chemospecificity hypothesis
• recognition molecules• Molecular matching predominates during embryon
ic development.• Activity (experience) modifies the circuits once the
y have been established.
Axon Guidance Cues from the target (wrong) series of discrete steps
• retina – optic fiber layer – retinal basal lamina and end-feet of glia – optic nerve head – optic stalk (‘pioneer’ axons) – optic chiasm - ventral diencephalon – superior colliculus at different subregions – - radial glial cells - synaptic partner – a specific layer – specific area of dendrites
Axon Guidance Cues
optic chiasm• different responses to special midline
cells• intermediate targets
terminal arbor• interaction with target• patterns of neural activity
Positional Cues
correction of ‘mistaken’ fibers• ephrins
rotation of neural tube between the chiasm and the tectum• markers of position or polarity
Motor Axon Guidance
series of discrete steps • motor pool in the spinal cord – segmental vent
ral roots by barriers in the somites – rearrangement in plexus region – large nerve – target muscle – synapse on a muscle fiber
similar pattern to the retinal fibers
Axon Growth: Options
grow / turn / stop positive and negative cues
• finer control over the direction of growth
Pioneers
short distance in a small embryo the first axons to exit the retina
Intermediate Targets
decision points optic chiasm, limb plexus
Gradients
cell surface molecules soluble molecules
Ranges of Cues
short-range cues• cell membranes• extracellular matrix• precise contact guidance
long-range cues• soluble molecules• less precise guidance
Growth Cone
Santiago Ramon y Cajal, 1890s “both a sensory structure and a motor structu
re” transduces positive and negative cues into si
gnals that regulate the cytoskeleton and thereby determine the course and rate of axon outgrowth
coupling between the sensory and motor capabilities
Growth Cone
central core• microtubules, mitochondria, etc
lamellipodia• motile, ruffled appearance
filopodia• long slender extensions
Filopodia
sensory capability rod-like, actin-rich, membrane-limited highly motile: advance, retract, turn length rapid movement flexibility
FilopodiaSecond Messengers
calcium• set point: optimal concentration• gradient of calcium: change of direction
cyclic nucleotides
modulate protein kinases, protein phosphatases, rho-family GTPases
Pathway Guidance Cues
promotion / inhibition cell surface / extracellular matrix / s
oluble form
Pathway Guidance Cues
extracellular matrix adhesion cell surface adhesion fasciculation chemoattraction contact inhibition chemorepulsion
ECM Adhesion collagen, fibronectin, proteogylcans, etc laminins
• heterotrimer, at least 14 trimers, unique distribution, position- or stage-dependent signals
integrins• heterodimer, at least 16 alpha and 8 beta chains, s
pecific ligands• all cells in the body: at least one integrin
Cell-Cell Adhesion selective adhesive interaction
cadherin: calcium dependent immunoglobulin-like adhesion molecules: calci
um independent
cell-cell binding short-range promoter of neurite growth
Cadherins
at least 100 related membrane-spanning glycoproteins
extracellular calcium binding segments N-cadherin, proto-cadherins, cadherin-relate
d neural receptors cells throughout the body
Cadherins
homophilic interaction• prefers to bind to its own kind• selective adhesion
Cytoplasmic domain binds catenins, then affects cytoskeletal elements.
Adhesion Molecules
adhesion assay Initial adhesion triggers a cytoplasmic rea
ction that strengthens the adhesion. not just adhesion molecules but ‘signalin
g molecules’ activated by membrane receptors
Ig Superfamily
disulfide bridges less ligand-specificity than cadherins intracellular domain: protein tyrosine phos
phatase or protein tyrosine kinase
Chemoattractants
soluble growth factors• trophic factor• chemotaxis: tropism
no clear examples of trophic and tropic factors in vivo
neuronal chemoattractants• two glycoproteins: netrins
Vertebrate vs. C. elegans netrin unc-6 unc-5H unc-5 DCC, neogenin unc-40
• Ig superfamily
remarkably conserved during evolution
Ephrins stripe assay axons from temporal retina to the anterior te
ctum heat treatment of each membranes
• heat treatment of posterior membrane: random growth
presence of inhibitory material in posterior membranes
Ephrins
repulsive axon guidance signal (RAGS) = ephrin A5
eph kinases: receptor tyrosine kinases major group of inhibitory ligands and rece
ptors in the developing nervous system
Ephrins ephrin A2 and ephrin A5 low-to high gradients in the rostral directi
on in the tectum eph A3 (a kinase receptor which binds ep
hrin A2 and A5) low-to-high gradient in the temporal direc
tion in retinal ganglion cells
Somaphorins
an inhibitory molecule at least 15 somaphorins in distinct types of neurons and non
neural cells key receptor: neuropillins, plexins
Chemorepulsion semaphorins
• some: membrane-bound• others: soluble factor
netrins• DDC or neogenin: attraction• unc-5H: repellant
Chemorepulsion
attract or inhibit according to the receptors or the level of intracellular messengers
some neurotransmitters• One synaptic transmission inhibits
formation of another.