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A BMS 381 - Developmental neurobiology > Cue integration and regeneration strategies > Flashcards

Cue integration and regeneration strategies Flashcards

1
Q

How are responses to cues modified?

A

1) Receptors for cues may interact to silence each other (DCC/Robo)
2) Modification to signals depending on the combination of cues received

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2
Q

What does the response to a cue depend on?

Example?

A

Depends on the CONTEXT

Eg. if a growth cone, depends if pre-crossing or post-crossing

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3
Q

What are cyclic nucleotides important in?

A

In determining the POLARITY of a growth cone’s response to chemotropic signals (ATTRACTED OR REPELLED)

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4
Q

What is cAMP activated by?

What does this do?

A

NGF activates cAMP

NGF turns growth cones in culture

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5
Q

What molecule of cAMP turns GC? Why?

A

db-cAMP (can cross the membrane)

cAMP cannot cross the membrane

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6
Q

Is higher [cAMP] attractive or repulsive?

A

Attractive

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7
Q

How can the polarity of response to a cue by reversed/negated? (2 ways)

A

1) By manipulating the concentrations of intracellular cyclic nucleotides
2) Reversed according to the combination of receptors present

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8
Q

What happens when block cAMP inside the cell

What does this show?

A

No activation of cAMP-dependant PKA
Reversal of the response to netrin

Shows:
- cAMP acts as a SWITCH, determining the polarity of the netrin response

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9
Q

How does [cAMP] and [cGMP] affect the polarity of response?

A

Binding to attractant (eg. netrin/NGF) - increases cAMP and decreases cGMP

Binding to repellant (eg. sema) - increases cGMP and decreases cAMP

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10
Q

When is DCC receptor involved in attractring/repelling?

A

Attractant - when bound to NETRIN

Repellant - when ACCOMPANIED to co-receptor Unc5
—-> causes netrin to become REPLLANT

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11
Q

When is netrin a repellant?

How does this act?

A

When its receptor DCC is accompanied by a coreceptor Unc5

Acts through the [cAMP]:[cGMP] balance

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12
Q

How do MAG and Nogo act as repellants?

How is this different to other repellants?

A

By INHIBITING cAMP

Other repellants (eg. sema, netrin (with unc5 coreceptor), ephrin) have their effect by INCREASING cGMP

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13
Q

How are cyclic nucleotide levels affected?

A

1) By extracellular cues
2) By the combination of receptors present
3) By signals from other receptors

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14
Q

What ligand binding to their receptor affect cAMP levels?

How?

A

Receptors binding to laminin or glutamate

Lowers cAMP levels

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15
Q

What ligand binding to their receptor affect cGMP levels?

A

Receptors binding to nitric oxide

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16
Q

What does how the GC behave depend upon?

A

COMBINATION of signals from the environment

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17
Q

How do specific environments alter guidance responses?

A

By modulating cyclic nucleotides

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18
Q

Describe the journey of retinal ganglion cells to/after the tectum

How are the neurons directed away from the ONH once they have crossed it?

A
  • Initially attracted by NETRIN to cells in the optic nerve head
  • After reach ONH - contact with LAMININ in the optic nerve –> REVERSES the response of the neurons to netrin (serves to direct neurons AWAY from the ONH and towards the tectum)
  • Lamanin receptors are members of the integrin family - SUPRESS cAMP when they signal
    (Lower cAMP –> REPULSION)
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19
Q

How does 14-3-3 alter the response of the cell to an attractive cue? (eg. shh)

A

14-3-3 INHIBITS PKA (which is normally activated by cAMP)

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20
Q

How does cAMP signal?

A

Through PKA

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21
Q

How does cGMP signal?

A

Through PKG

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22
Q

What are 2 inhibitory molecules that are implicated in the faliure of adult mammalian CNS to regenerate after nerve injury?

How do they do this?

A

1) MAG
2) Nogo

They LOWER/inhibit cAMP by activating RhoA

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23
Q

How can spinal cord injury be treated?

A

Manipulating cAMP and RhoA

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24
Q

Where does regeneration occur/not occur?

A

Occurs in LOWER vertebrates and the PERIPHERAL NS but not in the CNS

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25
What happens in the periphery during regeneration?
- Injury - MACROPHAGES move in and clear debris - Expression in the injured nerve of RAG (regeneration associated genes) - Proliferating SCHWANN cells --> promote axon regeneration
26
Why does the CNS fail to regenerate? (3 things)
1) Failure to activate growth promoting program in the injured neuron 2) Presence of INHIBITORY factors in the CNS myelin that disrupt axon extension 3) Formation of a 'Glial scar' - PHYSICAL barrier to for axon growth
27
When do CNS neurons have the capacity to regenerate? (2 things)
1) If given the APPROPRIATE SUBSTRATE | 2) If the RIGHT GENES are activated
28
When can retinal ganglion cells regenerate?
When they bypass the optic nerve and go down the sciatic nerve (which they don't normally do)
29
When can the neurons in the DRG regenerate/not regenerate?
In the PERIPHERAL branch but NOT in the CNS branch
30
What happens if cut the peripheral branch of the DRG axons a few days BEFORE cut the central branch? What does this show?
Leads to regeneration in the central branch as well as the peripheral branch Shows substrates and factors released from the periphery when cut can activate a regeneration program that can IGNORE CNS inhibition
31
What is the conditioning lesion? What happens if cut the CNS branch without the conditioning lesion?
Cutting the peripheral branch of the DRG NO regeneration
32
What do all the factors/receptors that inhibits CNS regeneration converge on?
RhoA
33
What ligands activate RhoA? What does this cause? How?
MAG, OMgp and NOGO All bind to NgR to change the RhoA/Rac balance Activates RhoA --> growth cone collapse and the inhibition of nerve fibre regeneration
34
How is RhoA inhibited? What does this allow?
By db-cAMP: - Increases cAMP - Activates PKA - PKA phosphorylates RhoA --> inactivation of RhoA
35
How does a pre-conditioning lesion allow regeneration in the CNS?
By elevation of cAMP
36
What happens when db-cAMP is administered in the presence of inhibitory myelin?
REGROWTH of neurons
37
What does db-cAMP injection into the DRG INSTEAD of the pre-conditioning lesion cause?
Regrowth of the cut CNS neuron
38
What 2 points of intervention have been used to try and allow regeneration in the CNS?
1) db-cAMP to elevate cAMP | 2) Activation of PKA pathway
39
What shows that cAMP alone is not enough to cause effective regeneration in the CNS?
- Treatment using db-cAMP has poor regeneration - Pre-conditioning lesion alone is MORE EFFECTIVE in promoting regrowth that db-cAMP treatment - Transcriptome following pre-conditioning lesion shows a LARGE ARRAY of changes/genes get switched on - CL induces GLOBAL increase in trafficking of many intracellular components into the injured cell branch that is NOT SEEN without CL or with cAMP alone
40
What genes get switched on following the CL?
RAGs (Regeneration-associated genes)
41
What intracellular components get trafficked into the injureed cell branch following the CL? What does this show?
- Mitochondria - MAPs - 14-3-3 proteins - RhoGDI - CRMP Shows: CL may affect the OVERALL POLARISATION in the cell
42
What does ROCK (Rho-kinase) inhibition cause?
Promotion of CST(corticospinal tract) regrowth
43
What is the CST?
Descending motor pathway
44
What is C3 transferase? How does this affect CST regrowth? How about Cethrin/VX-210?
INHIBITOR of RhoA Allows regrowth of CST neurons IN VITRO But NOT in vivo Cethrin/VX-210 - cell permeable C3 transferase, some success in animals
45
What is Y27632? How does this affect CST regrowth?
ROCK inhibitor Promotes regrowth of of the DC column when administered at the same time as the lesion
46
What affects does ibuprofen (NSAID) have on neuron regeneration? How?
Enhances DRG growth on myelin and CSPGs (a component of glial scars) By inhibiting RhoA activation a
47
What are CSPGs?
Chondroitin sulphate proteoglycan
48
What does ibuprofen cause? How?
Enhanced recovery DISTAL to the CST lesion (beyond lesion site) AND mild recovery of motor function By inhibiting RhoA activation in the injury site
49
How can see improvement of motor function in animals?
Increase stride length and reduce stride width BBB increase
50
Does ibuprofen work through the NORMAL NSAID pathway to cause spinal tract regeneration? How is this seen?
NO ``` Other NSAIDs (eg. Naproxen) doesn't have this affect Also other COX inhibitors do not work ```
51
How does ibuprofen cause regeneration of spinal cord tracts?
Activation of transcription factor (PPAR): --> up regulates a PHOSPHATASE (SHP-2) which: IHIBITS a RhoA GEF --> suppresses RhoA activation
52
What did Park et al suggest?
Pathways involved in regulating cell GROWTH may also regulate the ability of axons to grow (control regeneration)
53
What did Park et al do? Why did they do this in the retina?
Tested a pool of mice containing CONDITIONAL KOs of growth control genes for ability to regrow OPTIC NERVE after injury In the retina: - Easy to get to - RGCs project into the CNS - good paradigms for
54
What genes are involved in growth control?
P53 Smad4 LKB1 PTEN (antagonist for PI3K)
55
How are conditional KOs made?
- Mouse with floxed allele with loxP sites either side of gene to KO - Adenovirus carrying cre under control of a strong promoter into this mouse - Where ever virus goes - turn on cre and KO target genes (which are floxed)
56
How can follow the regeneration of a nerve?
Put GFP into the adenovirus
57
What did the conditional KOs of growth control genes that Park et al show? What does this show?
Only PTEN KO significantly enhanced neuronal survival, allowing retinal ganglion cell axon regrowth adult mice Shows PTEN normally REPRESSES axon growth
58
What pathway does PTEN regulate? How?
The mTOR pathway Through Akt
59
What is rapamycin? How does it work?
Immunosuppressant drug for organ transplantation Anti-proliferative drug (for treatment of cancer) Works by INHIBITING the mTOR function
60
What happens to mTOR pathway when development CEASES? What does this cause?
PROGRESSIVELY inhibited Causes levels of phospho-s6K to decrease (start high in development) As mTOR phosphorylates S6K --> p-S6K to DRIVE GROWTH
61
What does 'mTOR' stand for?
mammalian Target Of Rapamycin
62
What does p-s6K do?
DRIVES growth
63
What does a axotomised axon do to p-s6K?
DOWNREGULATES it
64
What activates mTOR? What does this cause?
Nutrients Causes mTOR to phosphorylate s6 KINASE --> phospho-S6K --> Growth
65
How does PTEN normally inhibit axon regrowth?
PTEN causes PIP3 --> PIP2 Less docking for Akt Akt NORMALLY inhibits TSC1 which inhibits Rheb Rheb NORMALLY activates mTOR NO inhibition of TSC1 by Akt --> allows inhibition of Rheb - -> lowers mTOR - -> less p-S6 which drives growth
66
What happens in PTEN KO?
PIP2 --> PIP3 Akt docked at PIP3 Akt INHIBITS TSC1 which normally inhibits Rheb Rheb no longer inhibited and can activate mTOR AXON REGROWTH
67
How was it shown that the mTOR pathway is affected by PTEN?
KO of TSC1: - Retinal axons allowed to grow (mTOR functional - TSC1 normally inhibits Rheb-->mTOR)
68
What is bad about PTEN KO to regrow axon?
No functional recovery reported
69
Why is it difficult to develop drugs that INHIBT PTEN (in order to drive axon regrowth)?
Because most drugs act to ACTIVATE PTEN, due to its anti-proliferative action (in cancer treatment)
70
When has db-cAMP treatment only been successful?
When administered BEFORE injury
71
Are results using RhoA inhibitors promising?
Yes! now in phase 2/3 clinical trials
72
What are 3 problems still need to overcome for axon regeneration?
1) Other approaches needed (eg. anti-inflammatories) to block GLIAL SCAR formation (still major barrier for axon regrowth) 2) Axons still need to find appropriate targets after regeneration
73
What are 3 drugs being trialed for axon regeneration?
1) RhoA inhibitors 2) Inhibitors of PTEN 3) db-cAMP

A BMS 381 - Developmental neurobiology (17 decks)

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