Axon Guidance - Department of Molecular & Cell...
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Axon Guidance • Multiple decision points along a growing axon’s 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 to navigate toward their ultimate targets • Sperry’s chemoaffinity hypothesis
Transcript of Axon Guidance - Department of Molecular & Cell...
Axon Guidance• Multiple decision points along a growing axon’s
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 ofcues at different points along their trajectories tonavigate toward their ultimate targets
• Sperry’s chemoaffinity hypothesis
A number discrete steps and decision points along the way…A. 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
The retinotectal projection: a point-to-point topographic mapinverted over A/P and D/V axes
Retina Tectum
Tessier-Lavigne, Cell 1995
Roger Sperry: rotation of retina - RGCs still make connectionsaccording to their original (intrinsic) positions
Normal Eye rotated 180o
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
Axons are guided by different types of guidance mechanismsExtracellular matrix adhesion Cell surface adhesion Fasciculation
Chemoattraction
Contact inhibition
Chemorepulsion
Con
tact
med
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dLo
ng R
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Axon growth cone is a sensory-motor structure thatrecognizes and responds to guidance cues
Santiago Ramón y Cajal1852-1934
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.
Growth cone extension
Filopodia extended
Microtubules fromcentral core advance
Cytoplasm collapsesto create newsegment of axon
Extracellular Matrix Molecules (Contact Mediated)
Laminins: major components ofbasal laminae and account formuch of the axon outgrowthpromoting ability of theextracellular matrix.
Heterotrimers of related α,β,andγ subunits (5 α, 4 β and 3 γgenes – at least 11 trimers hasbeen identified).
Integrins: Expressed on thegrowth cone, interacts withlaminin (16 α and 8 β genes).
Heterodimers of α and β,recognize different laminins.
Cell Adhesion Molecules (Contact Mediated)
Binds Ca2+
Binds catenins, linksto cytoskeletons
Cadherinsuperfamily
Immunoglobulin superfamily
Contact-Mediated RepulsionFriedrich Bonhoeffer’s 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
Wilkinson, Nat. Rev. Neurosci. 2001
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
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
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)
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
Robo receptors transduce a midline repulsive signal encoded in slitproteins and silence netrin-mediated attraction
