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