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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
Q

What happens in the periphery during regeneration?

A
  • Injury
  • MACROPHAGES move in and clear debris
  • Expression in the injured nerve of RAG (regeneration associated genes)
  • Proliferating SCHWANN cells –> promote axon regeneration
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26
Q

Why does the CNS fail to regenerate? (3 things)

A

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

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27
Q

When do CNS neurons have the capacity to regenerate? (2 things)

A

1) If given the APPROPRIATE SUBSTRATE

2) If the RIGHT GENES are activated

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28
Q

When can retinal ganglion cells regenerate?

A

When they bypass the optic nerve and go down the sciatic nerve (which they don’t normally do)

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29
Q

When can the neurons in the DRG regenerate/not regenerate?

A

In the PERIPHERAL branch but NOT in the CNS branch

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30
Q

What happens if cut the peripheral branch of the DRG axons a few days BEFORE cut the central branch?

What does this show?

A

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
Q

What is the conditioning lesion?

What happens if cut the CNS branch without the conditioning lesion?

A

Cutting the peripheral branch of the DRG

NO regeneration

32
Q

What do all the factors/receptors that inhibits CNS regeneration converge on?

A

RhoA

33
Q

What ligands activate RhoA?

What does this cause? How?

A

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
Q

How is RhoA inhibited?

What does this allow?

A

By db-cAMP:

  • Increases cAMP
  • Activates PKA
  • PKA phosphorylates RhoA –> inactivation of RhoA
35
Q

How does a pre-conditioning lesion allow regeneration in the CNS?

A

By elevation of cAMP

36
Q

What happens when db-cAMP is administered in the presence of inhibitory myelin?

A

REGROWTH of neurons

37
Q

What does db-cAMP injection into the DRG INSTEAD of the pre-conditioning lesion cause?

A

Regrowth of the cut CNS neuron

38
Q

What 2 points of intervention have been used to try and allow regeneration in the CNS?

A

1) db-cAMP to elevate cAMP

2) Activation of PKA pathway

39
Q

What shows that cAMP alone is not enough to cause effective regeneration in the CNS?

A
  • 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
Q

What genes get switched on following the CL?

A

RAGs (Regeneration-associated genes)

41
Q

What intracellular components get trafficked into the injureed cell branch following the CL?

What does this show?

A
  • Mitochondria
  • MAPs
  • 14-3-3 proteins
  • RhoGDI
  • CRMP

Shows:
CL may affect the OVERALL POLARISATION in the cell

42
Q

What does ROCK (Rho-kinase) inhibition cause?

A

Promotion of CST(corticospinal tract) regrowth

43
Q

What is the CST?

A

Descending motor pathway

44
Q

What is C3 transferase?

How does this affect CST regrowth?

How about Cethrin/VX-210?

A

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
Q

What is Y27632?

How does this affect CST regrowth?

A

ROCK inhibitor

Promotes regrowth of of the DC column when administered at the same time as the lesion

46
Q

What affects does ibuprofen (NSAID) have on neuron regeneration?

How?

A

Enhances DRG growth on myelin and CSPGs (a component of glial scars)

By inhibiting RhoA activation a

47
Q

What are CSPGs?

A

Chondroitin sulphate proteoglycan

48
Q

What does ibuprofen cause?

How?

A

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
Q

How can see improvement of motor function in animals?

A

Increase stride length and reduce stride width

BBB increase

50
Q

Does ibuprofen work through the NORMAL NSAID pathway to cause spinal tract regeneration?

How is this seen?

A

NO

Other NSAIDs (eg. Naproxen) doesn't have this affect
Also other COX inhibitors do not work
51
Q

How does ibuprofen cause regeneration of spinal cord tracts?

A

Activation of transcription factor (PPAR):

–> up regulates a PHOSPHATASE (SHP-2) which:
IHIBITS a RhoA GEF –> suppresses RhoA activation

52
Q

What did Park et al suggest?

A

Pathways involved in regulating cell GROWTH may also regulate the ability of axons to grow (control regeneration)

53
Q

What did Park et al do?

Why did they do this in the retina?

A

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
Q

What genes are involved in growth control?

A

P53
Smad4
LKB1
PTEN (antagonist for PI3K)

55
Q

How are conditional KOs made?

A
  • 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
Q

How can follow the regeneration of a nerve?

A

Put GFP into the adenovirus

57
Q

What did the conditional KOs of growth control genes that Park et al show?

What does this show?

A

Only PTEN KO significantly enhanced neuronal survival, allowing retinal ganglion cell axon regrowth adult mice

Shows PTEN normally REPRESSES axon growth

58
Q

What pathway does PTEN regulate? How?

A

The mTOR pathway

Through Akt

59
Q

What is rapamycin?

How does it work?

A

Immunosuppressant drug for organ transplantation

Anti-proliferative drug (for treatment of cancer)

Works by INHIBITING the mTOR function

60
Q

What happens to mTOR pathway when development CEASES?

What does this cause?

A

PROGRESSIVELY inhibited

Causes levels of phospho-s6K to decrease (start high in development)

As mTOR phosphorylates S6K –> p-S6K to DRIVE GROWTH

61
Q

What does ‘mTOR’ stand for?

A

mammalian Target Of Rapamycin

62
Q

What does p-s6K do?

A

DRIVES growth

63
Q

What does a axotomised axon do to p-s6K?

A

DOWNREGULATES it

64
Q

What activates mTOR?

What does this cause?

A

Nutrients

Causes mTOR to phosphorylate s6 KINASE –> phospho-S6K
–> Growth

65
Q

How does PTEN normally inhibit axon regrowth?

A

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
Q

What happens in PTEN KO?

A

PIP2 –> PIP3
Akt docked at PIP3
Akt INHIBITS TSC1 which normally inhibits Rheb

Rheb no longer inhibited and can activate mTOR

AXON REGROWTH

67
Q

How was it shown that the mTOR pathway is affected by PTEN?

A

KO of TSC1:
- Retinal axons allowed to grow
(mTOR functional - TSC1 normally inhibits Rheb–>mTOR)

68
Q

What is bad about PTEN KO to regrow axon?

A

No functional recovery reported

69
Q

Why is it difficult to develop drugs that INHIBT PTEN (in order to drive axon regrowth)?

A

Because most drugs act to ACTIVATE PTEN, due to its anti-proliferative action (in cancer treatment)

70
Q

When has db-cAMP treatment only been successful?

A

When administered BEFORE injury

71
Q

Are results using RhoA inhibitors promising?

A

Yes! now in phase 2/3 clinical trials

72
Q

What are 3 problems still need to overcome for axon regeneration?

A

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
Q

What are 3 drugs being trialed for axon regeneration?

A

1) RhoA inhibitors
2) Inhibitors of PTEN
3) db-cAMP

A BMS 381 - Developmental neurobiology (17 decks)

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