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BMS 249 - Developmental Neurobiology > Axon Guidance II > Flashcards

Axon Guidance II Flashcards

1
Q

What are filopodia?

A

Finger-like projections

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2
Q

What are lamellipodia?

A

Sheet-like cellular outgrowths

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3
Q

What are filopodia and lamellipodia important for?

A

Cell shape changes, migrating cells and growth cones

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4
Q

What are the 3 growth cone domains?

A
  • Central (palm)
  • Transitional
  • Peripheral
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5
Q

What are the 2 filamentous proteins in the growth cone?

A

1) Microtubules (tubulin)

2) F-actin (filamentous actin)

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6
Q

What is different about the F-actin in filopodia and lamellipodia?

A

In lamella:
- Actin bundles are crosslinked into a net

In filopodia:
- Actin bundles are polarised to form larger bundles, with a linear array

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7
Q

What is ‘treadmilling’?

A
  • Single actin subunits are added to the tips of the of filaments (F-actin)
  • In the peripheral domain, F-actin flows back
  • In the transitional domain, the filaments break down into single actin subunits
  • In the
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8
Q

Where does treadmilling occur?

A

In filopodia in a resting growth cone

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9
Q

What happens to the microtubules in the central domain during treadmilling?

A

They are dragged sporadically dragged into the filopodia

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10
Q

What happens to the movement of the microtubules in the central domain when the growth cone comes into contact with an attractive cue?

A

The microtubules are more dramatically dragged into the filopodia

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11
Q

What happens in the F-actin when the growth cone comes into contact with an attractive cue?

What does this cause?

A
  • F-actin tread-milling slows down and F-actin accumulates (increases in concentration)

The F-actin accumulation:

  • Stabilises the filopodium
  • Drags the microtubules into the back of the filopodium - stabilsing the microtubules
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12
Q

When a growth cue is encountered, where do F-actin and microtubules point towards?

How is this done?

A

Towards the growth cue

Reorganisation of the microtubules to completely establish and new growth direction

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13
Q

When a growth cue is encountered, what 2 key components lead to filopodial extension and reorientation of the microtubules, to point towards the growth cue?

A

1) MOLECULAR CLUTCH
- Cross-linking to the backwards flowing actin to arrest backwards flow
- Filopodia don’t shorten
- Results in forwards movement of the filopodia (get longer)

2) ACTIN-TUBULIN LINK
- Actin-myosin based link
- Pulls the microtubules into the wake of the extending filopodium

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14
Q

What was discovered when neurons of different types were mixed in culture?

What is this NOT due to?

A
  • Neurons fasciculated only with their OWN kind

- NOT due to attractive forces

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15
Q

What is the ‘growth-cone collapse’?

A
  • F-actin is destabilised
  • High to low levels of actin
  • Causes the growth cone to retract
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16
Q

When does ‘growth-cone collapse’ occur?

A

When the growth cone of an axon comes into contact with the axon of another neuron

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17
Q

When ‘growth-cone collapse’ occurs, what happens afterwards?

A

Growth cone moves in a different direction

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18
Q

What are semaphorins?

A
  • A family of inhibitory guidance cues which can be membrane bound or secretory (have a lipid anchor)
  • All have a strongly conserved semaphorin domain
  • Non-permissive contact repellants
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19
Q

What happens when add semaphorins to a growth cone?

A

It moves away, due to dramatic collapse of F-actin (Growth cone collapse)

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20
Q

What does an axon require to allow it to grow?

A

Must be able to attach to the substrate it is growing on

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21
Q

What is the relationship between strength of adhesion and the amount of axon growth on a substrate?

A

There is no simple relationship - substrate adhesion does not determine how fast an axon will grow

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22
Q

What are permissive substrates and why are they important?

A

Substrates which ALLOW growth

Important because attachment alone is not enough for axon growth

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23
Q

Between collagen and laminin, which substance is the most adhesive?

A

Collagen

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24
Q

Between collagen and laminin, which substance is the most permissive?

A

Laminin

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25
Q

In the eye, where is laminin localised?

What does this allow?

A

Localised in the optic nerve, from the retina to the tectum

Allows the growth of the retinal ganglion nerves to the tectum

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26
Q

Even though laminin is permissive, what information does it not provide?

A

Speed of growth

Direction of growth

(not instructive)

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27
Q

What does the blockage of receptors for laminin in the optic nerve cause?

A

Slows down the growth

But doesn’t change the direction of growth

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28
Q

What do gradients of laminin in vitro cause?

A

Nothing, they DO NOT direct axon growth

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29
Q

When is laminin permissive?

A

Within a specific concentration:

If the concentration is too high or low - there is NO axon growth

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30
Q

Where are permissive and non-permissive substrates found?

A

On axon surfaces

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31
Q

What are permissive and non-permissive substrates NOT involved in?

A

Attachment

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32
Q

When a growth cone collapses, what happens to the attachment on the surface, what does this imply?

A

Attachment remains - growth cone collapse doesn’t imply lack of adhesion

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33
Q

What can non-permissive factors do?

How is this done?

A

Channel axon growth

2 stripes of non-permissive factors can be expressed either side of the growing axon

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34
Q

How is semaphorin expressed in the grasshopper limb?

A

In stripes of Semaphorin I

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35
Q

What happens when a growth cone comes into contact with cells expressing semaphorin?

A

The growth turns (growth cone collapse)

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36
Q

How can semaphorins be inserted into them membrane of a cell and what are these molecules?

A

1) Membrane bound (contact attractants/repellants

2) Lipid anchors (can be secreted - chemoattractants/repellants)

37
Q

What happens if Sema I expression is disrupted in the grasshoppper limb?

A

Neurons stray into the wrong teritories

38
Q

What semaporin is expressed in mice limbs?

A

Sem3A

39
Q

What happens if Sem3A expression is disrupted in mice?

A

Neurons stray into the wrong territories

40
Q

For axon growth, what must there be a balance between?

A

Permissive and non-permissive factors

41
Q

What are ephrins?

A

Non-permissive ligands, which are all membrane bound (cell-surface molecules)

CONTACT REPULSION FACTORS

42
Q

What are the receptors for ephrins and what are they called?

A

Tyrosine kinases - Ephs

43
Q

How are ephrins and ephs expressed in the embryo?

A

In reciprocal patterns (one is expressed where the other is not)

44
Q

What are ephrins thought to be used for? (3 things)

A
  • To compartmentalise the embryo into discrete domains (eg.rhombomeres)
  • And to keep axons out of specific areas of the embryo
  • Make topographic maps
45
Q

What 2 things can non-permissive factors do to the paths taken by growth cones?

A
  • Can work with permissive factors to channel the growth cone
  • Can keep the growth cone out of specific regions of the embryo
46
Q

How do axons know which way to go?

A

Chemoattractants and chemorepellants, which act over long distances to direct axons in certain directions

47
Q

What are permissive substrates also called?

A

Contact attractants

48
Q

What are non-permissive substrates also called?

A

Contact repellants

49
Q

How was it known that the roof plate and floor plate are organisers?

A
  • Cut out the spinal cord and took the top half of it and lay it on its side
  • Commissural neurons grew ventrally, as they should do
  • If put an ectopic floor plate - axons turn towards the floor plate
50
Q

How was it known that it was a SECRETED molecule coming from the floor plate which organises neurons?

A

If put floor plate out of direct contact of the axons, they still grow towards the floor plate

51
Q

What do commisural axons do?

A
  • Take information from the sensory afferents in the DRG and relay this information up to the thalamus
  • They find their way to the floor plate and cross underneath it
52
Q

Where is the floor plate chemoattractant protein expressed?

A

Along the midline of the vertebrate nervous system

53
Q

What is the chemoattractant protein in the floor plate and how was it discovered?

A

Netrin

Discovered by biochemical purification and cloning

54
Q

What molecule is netrin similar to and how?

A

Laminin - can associate with the ECM

55
Q

How was it known that netrin attracts commisural axons?

A

Take cells artificially expressing netrin - axons are attracted

56
Q

What repels commisural axons?

A

BMP (bone morphogenic protein), expressed by the roof plate

57
Q

What is special about BMPs and Shh?

A

They are used in many stages of patterning the embyro.

At early stages:
- Pattern the DV axis and specify where neurons are BORN

At later stages:
- GUIDE axons, to their targets

58
Q

What does purified BMP7 do?

A

Cause growth cone collapse

59
Q

What happens in a netrin knockout?

A
  • Commissural axons reach the floor plate

- BUT, they do not cross the floor plate

60
Q

What 2 things are involved in guiding commissural axons to the floor plate?

A

BMP signalling from the roof plate

SHh signalling from the floor plate

61
Q

Why can BMP alone not direct commissural axons to the floor plate?

A

They cannot reach the ventral part of the neural tube

62
Q

What blocks shh signalling?

A

Cyclopamine

63
Q

What is needed for Shh signalling?

A

Smo receptors

64
Q

What does bacteriophage P1 encode and what does this allow the bacteriophage to do?

A

Cre recombinase

Allows the bacteriophage to insert its DNA into the host genome

65
Q

What does Cre do?

A

Binds to 2 loxP sites and joins them together

66
Q

What can Cre recombinase be used to do and how?

A

Specifically delete DNA (knockout)

  • Flank a DNA sequence wishing to KO with 2 loxP sites
  • When exposed to Cre recombinase will cut and rejoin the 2 loxP sites together
67
Q

What is flanking the gene with loxP sites called?

A

Floxing

68
Q

How can smo be knocked out ONLY in the commisural axons in an organism?

A

1) Flox a smo allele
2) Cross into a mouse with Wnt 1 promoter which drives cre recombinase (Wnt 1 is normally expressed in the roof plate)
3) Offspring will have smo allele removed only in the commisural axons (as they are derived from the dorsal lip of the neural tube) and the DRG (derived from the neural crest)

69
Q

Why is it important to only KO smo in commisural axons if wishing to study how it guides these axons?

A

Shh is important for development in the early embryo- if KO shh in the whole embryo the commisural axons will not form

70
Q

Where are commissural axons derived from?

A

The dorsal lips of the neural tube

71
Q

What is used to guide pioneer axons?

A

TF expressed in specific cells in specific domains in the environment which are set up by the early patterning information in the embyro (eg. BMPs Shh)

72
Q

How are morphogenetic gradients re-used to guide axon paths?

A

BMP and Shh specify nerual fate

BMPs and Shh co-operate with netrin to guide commissural axons

73
Q

How do long-range and short-range cues work together in the grasshopper limb to guide axons to their targets?

A

Sema2 is secreted in a decreasing gradient towards the body and guides the Ti1 axons - long range cue

Sema1 - short range cue

74
Q

How is Sema2 secreted in the grasshopper limb?

A

In a decreasing gradient, towards the body

75
Q

What does the blockage of Sema2 cause and what does this suggest?

A

Disruption of the initial guidance of the Ti1 axons towards the body

Suggests that the gradient of secreted Sema2 directs the Ti1 growth cone towards the body

76
Q

How are the four guidance cues used?

A

In combinations together, the guide axons at different stages in their pathway

77
Q

How are complex neuron pathways built up?

A

In several stages

78
Q

When axons reach their intermediate targets, what must they do?

A

Make navigational choices (these are choice points)

79
Q

In the grasshopper limb, what is a short range cue?

A

Sema I

80
Q

In the grasshopper limb, what is a long range cue?

A

Sema II

81
Q

Which part of the growth cone is and isn’t attached to the ECM?

A

Palm is attached

Filopodia is not attached

82
Q

How can sema1 function be blocked?

A

With antibodies

83
Q

Why would you want to control when cre recombinase is turned on?

A

So can control WHEN a certain gene is knocked out

84
Q

How big is the sequence of a loxP site?

A

34 base pairs

85
Q

Where is Wnt1 normally expressed?

A

In the roof plate

86
Q

What is lacZ?

What does it do?

A

A reporter gene

Marks the function or location of ANOTHER gene or function as its expression is easily monitored

87
Q

When using a Wnt1 gene to drive cre recombinase to knock out smo, where is smo knocked out and why?

A

KO in commisural axons and DRG

As Wnt1 is normally expressed in the roof plate

Commisural axons are derived from the dorsal lips of the neural tube and the DRG are derived from the neural crest

88
Q

Where do commisural axons derived from?

A

The dorsal lips of the neural tube

89
Q

If knock out Shh or Smo what happens?

A

Early embryonic lethal

BMS 249 - Developmental Neurobiology (16 decks)

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