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BMS381 Developmental Neurobiology > L3 - Gradients in Axon Guidance > Flashcards

L3 - Gradients in Axon Guidance Flashcards

1
Q

What is the gradient guiding c-axons from the roofplate to floorplate

A

ChemoREPELLENT BMPs from the roofplate

ChemoATTRACTANT Netrins from the floorplate

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2
Q

What is dorsal

A

Roof plate

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3
Q

What is ventral

A

Floor plate

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4
Q

Cells that express the NETRIN gene are able to

A

Turn c-axons

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5
Q

Most of the c-axons in mammals turn …

A

Rostrally

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6
Q

A rostal turn is from _____ to _______

A

Posterior to anterior

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7
Q

What are the two possibilities for WHY the c-axons make the rostral turn

A

AP gradient of chemoattractant vs repellent

Short range, non diffusible cue

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8
Q

What would be the prediction that could be made if the cue was diffusible vs non diffusible

A

A small explant will lose its gradient if the chemotrophic agent is diffusible (large explant won’t)

If the guiding factor was non diffusible then this would not be the case

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9
Q

Evidence from Journal club paper

What are the questions to identifying the candidate molecule

A

Right place right time
Suff
Nesc

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10
Q

How did the journal club paper identify Wnts as the candidate molecule

A

Only Wnts had any effect
Wnt4 expressed in a AP gradient in the FP
Wnt4 transfected cos cells can turn post crossing axons in either directions
Fz3 KO mouse has confused turns post floor plate
Wnt4 binds to Fzd3

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11
Q

Wnt gradients act over distances of …

A

At least few mm

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12
Q

What are the two ways a cell can detect gradients

A

Temporal detection

Spatial detection

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13
Q

What is temporal detection

A

Change in concentration over time

Cell must compare ammount of ligand at two different time points

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14
Q

What is spatial detections

A

Change in concentration across the cell (or growth cone)

Cell must compare the ammount of ligand at two different points on its surface

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15
Q

What mech of detection is likely to be most useful for SLOW MOVING EUKARYOTES

A

Spatial detection

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16
Q

What is the accuracy of orientation towards a source dependent on

A

The absolute concentration

Steepness of the concnetration gradient

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17
Q

When is the most accourate response seen. Why is this?

A

When absolute conc closest to Kd

Since will have half of the receptors occupied and will be easiest to detect change

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18
Q

What is the gradient expressed as

A

% change per um

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19
Q

A gradient of 0.2% is equivilant to a ____ change per 10um

A

2%

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20
Q

Cells with a ______ diameter oritent better than _______ cells in shallower gradeints

A

LARGER

SMALLER

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21
Q

What is amplification used for

A

To enhance sensitivity to gradients

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22
Q

What does amplificiation require

A

Local enhancement of signal together wirh inhibition of signal reception in other parts of the cell

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23
Q

Describe one suggest mechanism of receptor enhancement

A

Clustering of receptors/signalling components in region where receptors are activated by transporting components from another part of the cell

24
Q

Chemoattractants is leukocytes and dictostellium activate ____

A

PI3K via a GPCR

25
What are the keypoints from the chemoattractant induced signalling pathway in leukocytes and dictostellium
Chemoattractant detected by a GPCR (7TMD protein) Activation of PI3K causes phos of PIP2 --> PIP3 Provides a docking site for proteins with a PH domains such as Akt - localised signalling domain on the membrane
26
What is the action of PTEN WHy is this important
Antagonises action of PI3K Phosphatase that acts on PIP3 --> PIP2 Ensures signals highly localised and dependent on constant external activation
27
PHs domains are recruited to which part of a chemotaxing cell
LEading edge
28
What is the effect of a PI3 K inhibitor in neurones
Disruption of growth cone turning induced by netrin
29
Recent studies have shown PH domain proteins also localise in
Growth conesq
30
Describe the results of the experiment that showed PH domains proteins during growth cone stimulation
xenopus SC neurone expressing Akt-PH-GFP Turns in response to BDNF Can see fluctuations which shows the PIP3 labile nature to maintain its responsiveness
31
What type of vesicular transport occurs in growth cones in response to cues
Asymmetric
32
Describe the experiments that showed asymmetric vesicle transport was involved
Vesicles tagged with FM1 membrane dye Growth cone loaded with caged Ca UV flash causes release of Ca Vesicular transport to the source of Ca
33
Vesicles are seen associated with _____- suggesting ...
Associated with MT | Suggeests they are activeyl transported along MT
34
What is the second mechanism to enhance the range over which cues can be detected
Adaptation
35
Why is adaptation needed
Receptors saturate as concentration rises | Even the shallowed gradients required to turn a cell will result in 90% receptor occupancy
36
What is an example of adaptation as seen in normal physiology
Synaptic transmission signal saturation leads to sensitisation and the signal falls
37
Describe the frog axon turning assay
Using a Xenopus spinal cord neurone turning assay | Axons of isolated neurone from early emrbyonic Xenopus spinal cord respond to netrin pulsed into a dish from a pipette
38
Which lab performed the frog axon turning assay
Mu ming poo
39
Evidence for adaptation in the response to netrin
Pulsed netrin creates an exponential gradient revealed by including a fluro marker in pipette Growth cones zig zag Suggests an alternative pattern of attraction and repulsion = cycles of desenstisation and sensitisation of the grwoth cone to netrin
40
How was the pulsing netrin expeiment taken forward What (first) was the aim
To determine if GCs adapt to increasing attractant concentrations Ming et al. Pretreated axons with different concentrations of netrin
41
What were the results of Ming et al study pre treating the axons with netrin
Imm after treatment growth cones fail to respond After a longer period GCs resensitised Resensitisation dep on MAPK activation and local protein synthesis in the growth cone
42
what other molecule elicits a similar response of adaptation ....
Sema3A
43
what determines the distance that growth cones could be guided by gradients
Type of molecule and how the gradient is set up
44
Examples of diffusible molecules forming gdts
Wnt - expression gdt along an axis | Netrins - point source from the FP
45
Examples of non diffusible molecules forming gdts
Ephrins - surface bound molecules expressed in gradients
46
Poiint source (diffusible) gdts are typically __________ and have a theoretical max range of ________
Expo | 1mm
47
How does the theoretical max range of a point source grf correspond to what is seen in vivo
Roof plate (BMPs) and floor plate (Netrins) act over this distance
48
What do point sources depend on
Limited diffusion rate | Some mechanism for removing the guiding molecule
49
What happens if there isnt a mechanism for removing the molecule
Gdt will flatten over time
50
What is different in the linear substrate bound gradient
Can be much longer and has a theoretical max range of 1cm
51
How does the theoretical max range of a linear substrate bound gradient correspond to what is seen in vivo
Ephrins in the tectum
52
Describe the distribution of Netrin mRNA in the chick
Netrin1 localised to the floorplate | BUT netrin2 expressed throughout
53
How many netrin genes in mouse How does its expression pattern compare to that of the chick
Only single netrin gene | mRNA pattern is a combination of the chick genes with notable expression in the ventricular zone
54
What is the structure of the netrin protein, what does this suggest about it ... how is this confirmed by what is seen in vivo
lamin like structure might be bound in the ECM | Found associated with basement membrane of the spinal cord
55
What has recent evidence shown about the nessecity of Netrin
May not be required in the FP for C axon guidance
56
Is Wnt4 a point source
No likely to be graded expression - expression likely to vary temporally Expression likely to change from rostra to caudal (A-P) as dev proceeds

BMS381 Developmental Neurobiology (16 decks)

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