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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
Q

What are the keypoints from the chemoattractant induced signalling pathway in leukocytes and dictostellium

A

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
Q

What is the action of PTEN

WHy is this important

A

Antagonises action of PI3K
Phosphatase that acts on PIP3 –> PIP2
Ensures signals highly localised and dependent on constant external activation

27
Q

PHs domains are recruited to which part of a chemotaxing cell

A

LEading edge

28
Q

What is the effect of a PI3 K inhibitor in neurones

A

Disruption of growth cone turning induced by netrin

29
Q

Recent studies have shown PH domain proteins also localise in

A

Growth conesq

30
Q

Describe the results of the experiment that showed PH domains proteins during growth cone stimulation

A

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
Q

What type of vesicular transport occurs in growth cones in response to cues

A

Asymmetric

32
Q

Describe the experiments that showed asymmetric vesicle transport was involved

A

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
Q

Vesicles are seen associated with _____- suggesting …

A

Associated with MT

Suggeests they are activeyl transported along MT

34
Q

What is the second mechanism to enhance the range over which cues can be detected

A

Adaptation

35
Q

Why is adaptation needed

A

Receptors saturate as concentration rises

Even the shallowed gradients required to turn a cell will result in 90% receptor occupancy

36
Q

What is an example of adaptation as seen in normal physiology

A

Synaptic transmission signal saturation leads to sensitisation and the signal falls

37
Q

Describe the frog axon turning assay

A

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
Q

Which lab performed the frog axon turning assay

A

Mu ming poo

39
Q

Evidence for adaptation in the response to netrin

A

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
Q

How was the pulsing netrin expeiment taken forward

What (first) was the aim

A

To determine if GCs adapt to increasing attractant concentrations Ming et al.

Pretreated axons with different concentrations of netrin

41
Q

What were the results of Ming et al study pre treating the axons with netrin

A

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
Q

what other molecule elicits a similar response of adaptation ….

A

Sema3A

43
Q

what determines the distance that growth cones could be guided by gradients

A

Type of molecule and how the gradient is set up

44
Q

Examples of diffusible molecules forming gdts

A

Wnt - expression gdt along an axis

Netrins - point source from the FP

45
Q

Examples of non diffusible molecules forming gdts

A

Ephrins - surface bound molecules expressed in gradients

46
Q

Poiint source (diffusible) gdts are typically __________ and have a theoretical max range of ________

A

Expo

1mm

47
Q

How does the theoretical max range of a point source grf correspond to what is seen in vivo

A

Roof plate (BMPs) and floor plate (Netrins) act over this distance

48
Q

What do point sources depend on

A

Limited diffusion rate

Some mechanism for removing the guiding molecule

49
Q

What happens if there isnt a mechanism for removing the molecule

A

Gdt will flatten over time

50
Q

What is different in the linear substrate bound gradient

A

Can be much longer and has a theoretical max range of 1cm

51
Q

How does the theoretical max range of a linear substrate bound gradient correspond to what is seen in vivo

A

Ephrins in the tectum

52
Q

Describe the distribution of Netrin mRNA in the chick

A

Netrin1 localised to the floorplate

BUT netrin2 expressed throughout

53
Q

How many netrin genes in mouse

How does its expression pattern compare to that of the chick

A

Only single netrin gene

mRNA pattern is a combination of the chick genes with notable expression in the ventricular zone

54
Q

What is the structure of the netrin protein, what does this suggest about it … how is this confirmed by what is seen in vivo

A

lamin like structure might be bound in the ECM

Found associated with basement membrane of the spinal cord

55
Q

What has recent evidence shown about the nessecity of Netrin

A

May not be required in the FP for C axon guidance

56
Q

Is Wnt4 a point source

A

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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