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8/12/2019 Axon Guidance - Berkley Lecture
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Axon Guidance Multiple decision points along a growing axons
trajectory Different types of axon guidance cues:
Contact mediated - requires direct contact by growth cone Long range - growth cone responds to chemical gradient
Growth cones respond to these different types of cues at different points along their trajectories tonavigate toward their ultimate targets
Sperrys chemoaffinity hypothesis
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A number discrete steps and decision points along the wayA. To leave the retina at the otic nerve head (ONH)
B. To cross (or not) at the optic chiasm (and where)C. A/P and D/V positions
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The retinotectal projection: a point-to-point topographic mapinverted over A/P and D/V axes
Retina Tectum
Tessier-Lavigne, Cell 1995
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Roger Sperry: rotation of retina - RGCs still make connectionsaccording to their original (intrinsic) positions
Normal Eye rotated 180o
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Sperry: Chemoaffinity Hypothesis (1963)
1. Each position in the optic tectum has a unique molecularaddress or molecular tag
2. Each retinal ganglion cell (RGC) has a unique set of receptorsfor these tags (i.e., an identity), resulting in a position-dependent response dependent on differential affinities ordifferential intracellular responses
3. Unlikely to be unique molecules for each position (would beinsufficient information in the genome to wire up entire brainthis way) - rather, information is probably encoded inorthogonal gradients (A/P, D/V)
=> Positional identities of axons and targets are matched up toestablish the point-to-point topographic map
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Axons are guided by different types of guidance mechanismsExtracellular matrix adhesion Cell surface adhesion Fasciculation
Chemoattraction
Contact inhibition
Chemorepulsion
C o
n t a c
t m e
d i a t e d
L o n g
R a n g e
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Axon growth cone is a sensory-motor structure thatrecognizes and responds to guidance cues
Santiago Ramn y Cajal1852-1934
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Structure of the growth cone
Actin is concentrated infilopodia and lamellipodia
filopodiumlamellipodium
Microtubules areconcentrated in the centralcore of the growth cone
Filopodia sensory ability of the GC.
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Growth cone extension
Filopodia extended
Microtubules fromcentral core advance
Cytoplasm collapsesto create newsegment of axon
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Extracellular Matrix Molecules (Contact Mediated)
Laminins: major components of basal laminae and account for much of the axon outgrowthpromoting ability of theextracellular matrix.
Heterotrimers of related ! ," ,and# subunits (5 ! , 4 " and 3 #
genes at least 11 trimers hasbeen identified).
Integrins: Expressed on thegrowth cone, interacts withlaminin (16 ! and 8 " genes).
Heterodimers of ! and " ,recognize different laminins.
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Cell Adhesion Molecules (Contact Mediated)
Binds Ca 2+
Binds catenins, linksto cytoskeletons
Cadherinsuperfamily
Immunoglobulin superfamily
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Contact-Mediated RepulsionFriedrich Bonhoeffers stripe assay demonstrates sensitivity of posterior (temporal) retinal
axons to a repellent activity in posterior tectal membranes
Repulsive signalingmediated by theEphrins (ligand)and Eph receptors
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Wilkinson, Nat. Rev. Neurosci. 2001
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Manipulations of Ephrin Expression Alter Topographic Map
Normal: A -> PP -> A
Overexpress ephrinin spots in tectum:
A -> PP avoids areasw/ephrin
Reduced ephrin intectum:
A -> PP -> A, P
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Chemorepulsion (Long Range)Growth cone collapse upon exposure to a chemorepellent
Growth cone collapse from point source (gradient)leads to axon turning away from chemorepellent source
The Semaphorins and their receptors
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Chemoattraction (Long Range)
Netrin-1: secreted by the floorplate gradient guides axon turning
Netrin-1 receptor mediatingattractive response:
DCC - vertebrates, isevolutionarily conserved
= unc-40 - C. elegans (worms) = frazzled - Drosophila (flies)
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Response to netrin-1 is dependent on two factors1) Netrin receptors: DCC/unc-40/frazzled: attractive response DCC/unc-40 + unc5: repulsive response
2) cAMP levels and protein kinase A (PKA) activation
Netrin-1 can act as both chemoattractant and chemorepellent
High cAMP
low cAMP
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Robo receptors transduce a midline repulsive signal encoded in slitproteins and silence netrin-mediated attraction