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What is chemorepulsion?
- Long range guidance mechanism
- Growth cone collapse upon exposure to a chemorepellent
Growth cone collapse from point source (GRADIENT) leads to
Axon turning away from chemorepellent source
Semaphorin III can function as a
Selective chemorepellent to pattern sensory projections in the spinal cord
Crossing the midline
- Retinal ganglion cells at the optic chiasm
- Commissural axons in the spinal cord
NASAL retinal ganglion cell axons _____ the optic chiasm, whereas TEMPORAL axons ____ cross the optic chiasm.
- Nasal: DO cross
- Temporal: DO NOT cross
What is the optic chiasm?
Its where the X is, basically where the lines cross
RGCs in TEMPORAL retinal _____ EphB => ____ at optic chiasm by Ephrin B
RGCs in NASAL retina _____ EphB => _____ at optic chiasm
Netrin-1 (ligand): chemoattraction (long range)
- Secreted by the floorplate
- Gradient guides axon turning
Netrin-1 receptor mediating attractive response:
DCC: vertebrates, is evolutionarily conserved
Netrin-1 (unc6) in spinal cord
Secreted by the floor plate, attracts commissural axons toward ventral midline
In the spinal cord explants assays, commissural neurons grow toward ____
Adjacent floorplate or Cos cells expression netrin-1
Attraction to a gradient of netrin requires
Netrin-1 can act as both ___ and ___
Chemoattractant and chemorepellent
Response to netrin-1 is dependent on two factors
- 1) netrin receptors
- 2) cAMP levels and protein kinase A (PKA) activation
What are two netric receptors? What kind of response does each give?
- 1) DCC/unc40/frazzled: attractive response
- 2) DCC/unc40 + unc5: repulsive response
What do robo receptors do?
Transducer a midline repulsive signal encoded in slit proteins and silence netrin-mediated attraction
The axon growth cone can respond to multiple cues along its trajectory
Summary: Axon growth cones navigate their environment using the following mechanisms
- Contact mediated adhesion
- Contact mediated repulsion
- Long range chemoattraction
- Long range chemorepulsion
Summary: sperrys chemoaffinity hypothesis involve the following
- Molecular addresses or tags in the target
- Receptors for these tags expressed by incoming axon
- Must be a way to simplify the nature of the target-derived tags (gradient)
Summary: whether and how an axon growth cone responds to a cue depends on:
- The receptors it expresses at a given moment in time
- cAMP (and cGMP) levels, which can switch the growth cones response between chemorepulsion and chemoattraction
What will help the RGC decide whether or not to cross the midline?
- The same molecules that help dictate where RGCs in the retinal project to in the tectum
- EphB1 receptor
- EphrinB1 ligand
Where is EphrinB1 expressed? EphB1? What type of relationship is this?
- EphrinB1 ligand: Expressed in the OPTIC CHIASM
- EphB1 receptor: is expressed in the TEMPORAL RGCs
- Inhibitory relationship: so temporal RGCs wont cross the midline
Do nasal RGCs contain EphB1 receptor? What does this mean?
No, so they CAN cross the midline
Either the cell is REPELLED from the midline and wont cross, or it will be INSENSITIVE to it, and will be targeted contralaterally, following other chemoattractants cues in the tectum
What if you wanted an attractant cue across the mindline?
You would have to make sure whatever is attracted at the midline doesnt stay there or keep crossing over the midline. Specific cells would have to express the necessary receptors to be attracted to the midline in order to cross it
In the diagram, there are two cells, one goes on one side of the spinal cord and the other on the other side (dorsal/ventral). What differentiates these two cell types?
The expression of DCC and ROBO PROTEINS
Why are DCC and ROBO proteins important?
- Bc they are receptors for two signaling proteins expressed across the midline
- 1) NETRIN: expressed from the floorplate of the notochord
- 2) SLIT: expressed across the midline by midline glia cells
Netrin is a _____ of _____ and Slit is a ______ of ______
- Netrin: is an attractant of DCC
- Slit: is a repellent of Robo
What is the interesting fact about Netrin?
It can be both an attractant and a repellent depending on the specific receptors, and even the amount of PKA activity/cAMP levels
So when is Netrin an attractant and when is it a repellent?
- Attractant: when PKA is active and cAMP levels are high
- Repellent: when PKA is inactive and cAMP levels are low
What is the first thing that happens when the neuron crosses the midline?
- The DCC receptor is ATTRACTED toward the high levels of NETRIN coming from the floorplate of the notochord
- They are also INSENSITIVE to the SLIT that is expressed at the midline
Robo1 vs Robo3
- Robo1 receptors: although would be repelled by slit, are not active
- Robo1 is inhibited by another robo protein, ROBO3
- Robo3: prevents the repellent signal from affecting the axon
In pre-crossing axons, Robo3 levels are ____ and Robo1 levels are ____
- Robo3 levels are HIGH
- Robo1 levels are LOW
What will drive the axon to travel up the gradient of netrin?
- The two signals:
- 1) Attraction to NETRIN
- 2) no repellent signal from SLIT
- It will go toward the floorplate and begin to cross over
As the axon crosses over the midline, ROBO3 levels ____ and ROBO1 levels ____
- Decrease: Robo3 levels (possibly caused by high slit signals or high netrin signals)
- Increase: Robo1 levels (bc inhibition of Robo1 is lost
Robo1 will inhibit DCC. An active repellent signal from the midline and an inactive attractant signal so the axon will then start to be repelled, sending it over.
- If this happens as the axon is crossing over the midlne, it will become repelled from the midline as its moving over, keeping it on the other side, and preventing it from crossing back over
- NOTE: this should answer the question, why did the axon cross the midline, and only once?
What happens in precrossing and post crossing?
- In precorssing, Robo3 levels are high, and inhibits Robo1 which is low and can no longer inhibit DCC so attraction happens
- In postcrossing, Robo3 levels are low, so it cannot inhibit Robo1 which is now high and can inhibit DCC so attraction doesnt happen and repulsion happens