axon guidance - berkley lecture

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

axon guidance - berkley lecture

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