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BMS381 Developmental Neurobiology > L5 - Cue Intergration and Regeneration Strategies > Flashcards

L5 - Cue Intergration and Regeneration Strategies Flashcards

1
Q

What are able to turn growth cones in cultures

A

Analoges of cNMPs

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2
Q

Why can cAMP not turn grow cones

What must be used instead, why?

A

Because it is unable to cross membranes

db-cAMP must be used - membrane soluble version

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3
Q

How can the response to guidance cues be reversed?

A

By manipulating the concentrations of IC cyclic nucleotides

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4
Q

How can the dependence on cAMP by netrin be seen

A

Inhibit activity of cAMP-dependent protein kinase A –> NETRIN ATTRACTION NOW BECOMES REPULSION

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5
Q

What can be used to inhibit PK-A

A

KT5720

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6
Q

The effect of cAMP was ____ or _____- this suggests that ….

A

All or nothing!

Suggests that cAMP acts as a switch determine the polarity of the netrin response

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7
Q

In the context “determining the polarity of the netrin response” what does polarity mean

A

Whether the response is that of attraction or repulsion

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8
Q

What is the crucial balance in terms of guidance cues

A

Balance between [cAMP]/[cGMP]

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9
Q

How can responses to a specific cue be reversed …

A

According to the combination of receptors

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10
Q

Give an examle of how response to a cue can be manipulated according to the combination of receptors present

A

Netrin is attractive if using DCC

But is repulsive if DCC is accompanied by the co-receptor Unc5

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11
Q

How does MAG and NOGO work

A

By inhibiting cAMP

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12
Q

Increase in cAMP and decrease in cGMP leads to

A

Attraction

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13
Q

Decrease in cAMP and increase in cGMP can lead to

A

Repulsion

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14
Q

Modulators such as laminin and glutamate

A

Increase the levels of cAMP

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15
Q

Modulators such as NO

A

Can increase levels of cGMP

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16
Q

Modulators such as NOGO and MAG

A

Inhibit cAMP (decrease levels of)

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17
Q

In the initial stage of the journey to the tectum RGCs are _________ by ______ expressed by cells in the optic nerve head

A

Netrin Attracted

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18
Q

However after cotnact with _________ the ONH ________ the repsonse to ________

This acts to…..

A

Laminin

Reverses repsonse to netrin

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19
Q

Laminin receptors are members of the

A

Integrin family

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20
Q

When the integrin family of receptors signal what is their effect

A

Supression of IC cAMP

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21
Q

What are the two main inhibitory molecules of CNS myelin

A

MAG and NOGO

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22
Q

How does MAG and NOGO contribute to decreasing cAMP

A

Activation of RhoA leads to an increase in cGMP and a decrease in cAMP

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23
Q

CNS regeneration failure is due to

A

Failure to activate a growth promoting program in injured neurone
Presence of inhibitory factors in CNS myelin
Formation of Glial scar that acts as a physical barrier to grwth

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24
Q

CNS axons can only regenerate if (2)

A

Given the appropriate substrate

Right genes activated

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25
Q

If you cut a peripheral branch of DRG axons, then cut central branch of the SAME DRG axons what happens

A

Central as well as peripheral branch regeneration

26
Q

In this experimental paradigm what was the cut to the peripheral branch called?

A

Conditioning lesion

27
Q

What is MAG

A

Myelin associated glycoprotein

28
Q

NOGO and MAG all feed into

A

RhoA

29
Q

What is the effect of ibuprofen on RhoA

A

It inhibits RhoA

30
Q

What is the effect of RhoA on ROCk and on nerve fibre growth

A

RhoA activates ROCK which then BLOCKS the growth of nerve fibres

31
Q

Activation of the NOGO receptor changes with the ….

A

RhoA/Rac balance

32
Q

What 3 substrates are their for the NgR

A

MAG
OMgp
Nogo-A

33
Q

RhoGDI/RhoGEF leads to what effect in the Rac/RhoA balance

A

Increase RhoA and decrease Rac

34
Q

Effect of Rho activation

A

Activation of ROCK then growth cone collapse

35
Q

What is the effect of db-cAMP on RhoA - Rock

A

Activation of PK-A

Phosphorylation and INACTIVATION of RhoA

36
Q

How to Rho GDIs work?

A

Prevent dissociation of GDP from RhoA thus dampen the ability of a cell to activate

37
Q

Preconditioning peripheral lesion does what

A

Elevate cAMP levels

38
Q

What is the effect of a db-cAMP inection into the DRG prior to the lesion

A

Can enhance regrowth

39
Q

What is more effective: conditioning lesion or db-cAMP treatment

A

Conditioing lesion is more effect

40
Q

What was the major effects of the conditioning lsion

A

Turning on of regeneration associated genes

41
Q

Other effects of the conditioning lesion

A

Global increase in trafficking of numerous intracellular components into the injured branch that is not seen without CL or with cAMP

42
Q

Conditioning lesion may affect

A

The overall polarity of the cell

43
Q

What did Fournier et al test?

A

Regrowth in a different injury paradigm, involved the dorsal column lesion but monitoring the regrowth of the CST

44
Q

What is C3 transferase

A

RhoA inhibitor

45
Q

What is the effect of C3 transferase

A

Does affect regrwoth in cultured neurone but not in vivo

46
Q

What when applied at the same time as the CL does promote regrowth throguh yhr DC lesion

A

Y27632

Rock inhibitor

47
Q

What is clethrin

What is its function

A

A cell permable version of C3 transferase

RhoA inhibitor

48
Q

What is the affect of apllying clethrin

A

Works in animals - entering clinical trials

49
Q

What is the effect of Ibuprofen on regeneration

A

Enhances DRG growth on myelin and CSPGs
Inhibits RhoA activation in the injury site
Enhanced recovery distal to spinal cord hemi-section (CST lesion)

50
Q

What was the effect of ibuprofen on motr function

How was this measured

A

Mildly enhances recovery of motor function

Using the BBB score - a multi parameter measure of motor function

51
Q

Do all NSAIDs enhance regeneration

A

No

52
Q

Which NSAID enhances regeneration, which one doesnt

A

Ibuprofen does

Naproxen doesnt

53
Q

The fact that other COX inhibitors dont work suggests what

A

That this is not the normal NSAID pathway that is involved

54
Q

How then does ibuprofen work in this situation

A

Activation of the transcription factor PPARy which upregulates and phosphatase SHP-2 which inhibts a RhoA GEF to supress RhoA activation

55
Q

What were the controversial reuslts of the Lee et al 2010

A

Triple mutant mice for NOGO MAG and OMgp failed to exhibit enhanced regeneration of either axonal tract after the spinal cord injury

56
Q

What did Park et al deduce about signalling in growth and in regeneration

A

Pathways involved in regulating cell growth may also regulate the ability of axons to grow

57
Q

What were the methods used by Park et al

A

Test a pool of mice carrying conditional knockouts for major GROWTH CONTROL GENES: Rb, P53, SMAD4, LKB1 and PTEN for their ability to regrow the optic nerve after injury

58
Q

What were the reuslts of Park et al study

A

PTEN KNKCOUOT significantly enhanced neuronal survival and allowed the regrowth of retinal ganglion axons in adult mice

59
Q

How does PTEN enchance neuronal survivial

A

Regulation of the mTOR pathway

Axotomised axons downregulate p-s6 which is the mTOR branch of the pathway that is effected. Shown by the deletion of TSC-1 which allowed axons togrow

60
Q

Deletion of what gene enhanced regrowth of axons in the spinal cord

A

pten

61
Q

What is the issue with developing a drug to inhibit PTEN

A

Most drugs made activate it - as inactivated in many cancers (tumour supressor gene)

BMS381 Developmental Neurobiology (16 decks)

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