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A BMS 381 - Developmental neurobiology > How neurons develop their shapes > Flashcards

How neurons develop their shapes Flashcards

1
Q

How are axons and dendrites FUNCTIONALLY distinct?

A

Dendrites:
- Collect and integrate incoming information

Axons:
- Carry information away from the cell body in action potentials

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2
Q

How are axons and dendrites STRUCTURALLY distinct?

A

Axons:
- Highly polarised microtubules

Dendrites:
- Microtubules are LESS ORDERED and have MIXED ORIENTATION

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3
Q

How are axons and dendrites MOLECULARLY distinct?

A

Have DIFFERENT MAPs

Axons: Tau

Dendrites: MAP2

These MAPs cross-link MTs DIFFERENTLY

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4
Q

What are MAPs and why are they needed

A

Microtubule assembly proteins needed to stabilise microtubules

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5
Q

How do MAP stabilise microtubules?

A

Cross-link them into bundles

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6
Q

What are the MAPs in axons?

A

Tau

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7
Q

What are the MAP in dendrites?

A

MAP2

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8
Q

How is the plasma membrane organised?

A

COMPARTMENTALISED both intracellularly and on the cell membrane

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9
Q

What is L1?

A

An adhesion molecule that is restricted to AXONS

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10
Q

What is GluR?

A

Glutamate receptor that is restricted to the CELL BODY and DENDRITES

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11
Q

How is L1 restricted to the axon?

A

It is inserted at the GROWTH CONE as the growth cone grows

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12
Q

What is the experiment to show how surface separation is maintained?

What were the results?

What is the conclusion?

A
  • Bead coated with antibodies for L1 or GluR1
  • Drop bead onto dish - sticks via antibody to the component interested in
  • Use optical tweezers (laser) to move the bead around in the dish
  • Measure the force involved in moving the bead

Results:

  • Move L1 beads easily in axonal domain
  • L1 beads cannot cross the axon hillock
  • Cannot move Glut1 into the axon

Conclusion:
- PHYSICAL DIVISION between the dendritic and the axonal domain

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13
Q

How is the physical division between the dendritic and the axonal domain formed?

A

Due to interaction between the CELL SURFACE molecules and the UNDERLYING CYTOSKELETON

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14
Q

What is the experiment that shows how neuron polarity is set up?

What was seen?

A

Dissected hippocampal neurons dissociated from early mouse embryo and watched them develop

Seen:

  • Initial sprouts and immature neurites
  • Ultimately one neurite becomes DOMINANT - growth cone extends away
  • Neurites not selected become DENDRITES
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15
Q

What is a neurite?

A

ANY projection away from the cell body

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16
Q

What molecules are used to mark where axons are forming?

A

GFP-labelled + end directed kinesins (Kif-1)

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17
Q

What is critical for axon initiation?

How does this occur?

A

Microtubule stabilisation:

  • Growth cones and neurites contain DYNAMIC/UNSTABLE microtubules
  • Newly polarised axon contains STABILISED microtubules
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18
Q

What is the difference between dynamic and stabilised microtubules?

A

Dynamic microtubules are TYROSINATED

Stabilised microtubules are ACETYLATED

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19
Q

How can an axon be artificially chosen?

What does this suggest?

A

Artificially stabilise MTs using TAXOL treatment of one neurite

Suggests:
- Competition between neurites to stabilise their MTs

  • Some come of kind of feedback loop to SUPPRESS other neurites from becoming axons once a decision has been made
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20
Q

What happens when cut oft the growth cone of a neuron in culture?

What does this show?

A

Another neurite becomes the growth cone

Shows there is a FEEDBACK LOOP to supress other neurites from becoming axons

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21
Q

What is the feedback loop involved in the choice of a neurons?

A

BOTH positive and negative:

Positive - reinforce decision to become an axon at the growth cone

Negative - to the rest of the cell

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22
Q

What are the two theoretical models of feedback that prevents other neurites from becoming a neuron (negative feedback)?

What is common in both models?

A

A) Diffusible molecule released into the cell

B) Something LIMITING in the cell that is needed to form the axon - taken into the chosen neurite and is in LIMITED supply (cannot be used elsewhere)

In common: requirement for a positive feedback to AMPLIFY signal for axon formation

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23
Q

What does over expression of HRas cause?

What does this suggest?

A

Results in multiple neurons

Suggests that Hras is involved in neurite selection

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24
Q

What happens to HRas as the growth cone forms?

What is this consistent with?

A

HRas accumulates in the growth cone and is depleted from the rest of the cell (shipped down the axon)

Consistent with the idea of a limited component

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25
Q

What does activating PI3K do to HRas?

What happens to PI3K when HRas is activated?

A

ACTIVATES HRas

When HRas is activated - upregulate PI3K (feedback loop)

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26
Q

What blocks HRas accumulating in the growth cone as it forms?

What does this show?

A

PI3K inhibitor blocks HRas accumulation in the growth cone

Shows HRas stabilisation in the growth cone is dependant on PI3K

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27
Q

What happens downstream of PI3K?

A

PI3K elevates PIP3 levels in the membrane

PIP3 phosphorylated GSKbeta and Akt

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28
Q

Where is PIP3 present?

A

In the GROWH CONE (not in the immature neurites)

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29
Q

What does PIP3 affect? How?

A

Affects microtubules via PIP3 effects on Rac which act on actin

Through inhibiting GSKbeta

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30
Q

How does PIP3 inhibit GSK3beta?

A

In 2 ways:

  • DIRECTLY through phosphorylation
  • Via PHOSPHORYLATION of Akt, which is activated by PIP3
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31
Q

What does GSK3beta normally do?

A

Normally INHIBITS microtubule stabilisation - keeping the MT in a dynamic state

32
Q

How does GSK3beta regulate microtubule stability?

A

By differentially modulating microtubule association protein activities

33
Q

What happens to the microtubules when GSK3beta is inhibited?

A

Inhibition of stabilisation is inhibited

–> stabilisation of the microtubules

34
Q

How does PIPK effect the Par3 complex?

A

It PROMOTES Par3 complex accumulation in the growth cone

35
Q

What is the Par3 complex involved in?

A

Involved in asymmetric cell division

36
Q

Where was the Par3 complex discovered?

A

In c.elegans

37
Q

What happens if inhibit PIP3 accumulation?

A

Prevent Par3 accumulation in the growth cone - restricted to the cell body

PREVENTS AXON FORMATION

38
Q

What inhibits PIP3 accumulation?

A

PTEN

39
Q

What are SAD kinases?

A

Par1-related proteins

40
Q

What happens when KO SAD kinases?

Why does this happen?

A

Everything become NEURITES and axons do not form

Faliure of acetylated tubulin (stablised) to predominate over tyrosinated tubulin (dynamic)

41
Q

What are SAD kinases important in?

A

Specifying axons

42
Q

What is LKB1 kinase?

What happens if KO

A

Par4-related protein

Faliure to make axons

43
Q

What happens in Par-titioning defective genes?

A

Mutants fail to develop asymmetric cell divisions

44
Q

How does the Par complex initiate polarisation?

A

Through mutually antagonistic interactions of the Par3 complex with the Par1/2 complex

This affects microtubule organisation downstream

45
Q

Describe the interaction between PI3K, Par3 complex, GSKbeta ,LKB1 and SAD kinase to lead to axon specification

A

PI3K phosphorylates Par3 complex

Par3 complex INHIBTS GSK3beta (which normally inhibits axon formation) –> axons form

46
Q

What does LKB1 normally do?

A

Normally INHIBITS the Par3 complex, meaning GSK3b can function to inhibit axon formation

47
Q

What does phosphorylation of LKB1 cause?

A

Inhibits LKB1, inhibiting the inhibition of the Par3 complex, Par3 inhibits GSK3b –> axons can form

ALSO:
ACTIVATES SAD kinase

48
Q

What is SAD kinase required for?

A

Axon specification

49
Q

How does a neuron become polarised?

A

Inherits polarisation from the division, either:
- Inherited from the cell born from
OR
- From information from the apical basal environment they are in

50
Q

What phosphorylates LKB1?

A

PKA

51
Q

Where is LKB1 found?

Where is phosphorylated LKB1 found?

What is this consistent with?

A

LKB1: Found EVERYWHERE in the neuron

Phosphorylation LKB1: Restricted to the AXONAL compartment

Consistent with the fact that LKB1 is involved in POLARISATION

52
Q

What happens if KO LBK1?

A

No axonal polarisation

53
Q

Do factors promoting axonal polarity in vitro have effect on axon initiation when they are KO?

A

No

54
Q

What medical conditions disrupt neuronal progenitor migration?

A

Lisencephaly

Tublinopathies

55
Q

What is associated with TGFbeta receptor mutations?

A

Mild MENTAL RETARDATION

56
Q

Where are TGFbeta receptors expressed?

A

In the ventral zone of the developing cortex

57
Q

What does TGFbeta do in vitro?

What happens in TGFbeta KO?

A

Initiates axons

In KO - doesn’t initiate axons

58
Q

In a stripe assay with TGFbeta, where do axons/dendrites go/avoid?

A

Axons grow on TGFbeta

Dedrites AVOID TGFbeta

59
Q

What does TBFbeta affect in the par complex?

A

Affects Par6

60
Q

What are semaphorins?

What do they cause?

A

INHIBITORY guidance cues

Cause GROWTH CONE collapse

61
Q

What are the different types of semaphorins? (examples)

A

Membrane-bound (in the retina)

Secreted (Sema3A)

62
Q

Where is Sema3A expressed?

What does it do in the basal region?

A

In a GRADIENT from basal to apical

In the developing cortex:
Attracts dendrites
Suppresses axons

63
Q

What does Sema3A do in stripe assay?

A

Promotes dendrite formation

Suppresses axon formation

64
Q

Where do axons form in Sema3A stripe assay?

A

Where there is no Sema3A

65
Q

How does Sema3A afect [cGMP] and [cAMP]?

How does this affect axon formation?

A

INCREASES [cGMP]
INHIBITS [cAMP]

Therefore INHIBTS PKA phosphoylation of LKB1
Allows the GSK3beta to function
Preventing axon formation

66
Q

What does PKG affect levels of?

A

cGMP

67
Q

What does cGMP do?

A

Promotes DENDRITE formation

68
Q

What does cAMP do?

A

Promotes AXON formation

69
Q

What are par complex proteins involved in?

A

Apical basal polarity

Crawling cells

70
Q

Where is the Par3 complex localised?

A

In the LEADING EDGE

In the GROWTH CONE

71
Q

How does TGFbeta affect the Par6 complex?

What does this cause?

A

Phosphorylates Par6

PROMOTES axon formation

72
Q

Where does TGFbeta phosphorylate Par6?

A

APICALLY

73
Q

What happens basally in the developing developing cortex?

A

Sema3A increases [cGMP] and inhibits [cAMP]

Inhibits phosphoylation of LKB1 and axon formation

74
Q

Where is polarity inherited?

A

In the early cortex and in the retina

75
Q

What happens to polarity in later stages of cortical development?

A

Transit amplifying cells produced with NO polarity (polarity lost during division)

Polarity must be re-established before neurite selection

A BMS 381 - Developmental neurobiology (17 decks)

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