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Axon guidance Flashcards

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1
Q

how many neurons are in the human brain?

how many connections do each of these make? how many connections does that make in the brain?

A

10 to the power 11 neurons
each of these makes 1000 connections each
meaning there’s 10 to the power of 14 connections

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2
Q

how many extreme hypothesis theories are there for how the specific neuronal connectivity of the adult organism arises? name each one and say who proposed it.

A

there was 2 :
the resonance theory - Weiss
the chemoaffinity theory - Sperry

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3
Q

what is the resonance theory?

A

that stochatic (random) and diffuse neuronal outgrowth occurs to all targets followed by elimination of non- functional connections

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4
Q

what is the chemoaffinity theory?

A

that directed and specific outgrowth occurs through axons following “individual identification tags”carried by the cells and fibres of the embryo.

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5
Q

what happened during sperry’s experiment in 1963? what did this show? what has to be remembered?

A

the optic nerve was cut and the temporal retina removed.
this allowing just nasal axons to grow back
this proved that Sperry was right because the axons grew back directly to the right place, they ignored the territory that was normally innervated by other axons.
have to remember that this was during regeneration

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6
Q

If weiss was right how would you expect the axon pathways to be patterened?

A

Randomly

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7
Q

what is the pattern of axon outgrowth like?

A

it’s highly organised, reproducible and stereotyped.

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8
Q

what happens if in a chick embryo you cut and replace or reverse a segment of the neural tube before the motor axons grew out? what does this suggest?

A

despite displacement of cell bodies the motor axons T7 and LS1 still find their way to their normal muscle target.
this strongly suggests that axons can navigate to their targets.

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9
Q

what does the environment contain that allows axons to find their correct targets?

A

Guidance cues.

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10
Q

what is Cajal’s growth cone?

A

the growing tip of the axon which can sense cues in the environment.
this was proposed by cajal

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11
Q

why were early experiments on guidance cues done in insects?

why the grasshopper in particular?

A

because insects:
have a relatively simple NS
the embryos are easy to observe and manipulate.
the grasshoper was used as it’s larger this means that individual cells can be ablated using lasers.

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12
Q

what did early experiments to identify the locations of guidance cues find about axons pathways?

A

found that pathways by axons are stereotyped both from embryo to embryo and also from segment to segment

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13
Q

in the grasshoper what did detailed analysis of the experiment to locate guidance cues result in?

A

resulted in the identification of almost every neuron in the embryonic nerve cord, allowing a map of axon projections to be made.

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14
Q

what did reproducibility of axon behaviour in the grasshopper suggest?
when did pathways seem to change?
how was this tested?

A

suggested that growth cones responding to cues in the environment
the pathways seem to change when specific axons are encountered
this was tested by ablating cells that might carry potential cues.

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15
Q

during laser ablation, how can it be proved that the G-axon growth is looking for specific cues on the P - axon?

A

ablate the p - axon, the g-axon will stall.
know it’s not because of having a lack of axons to extend on to because there’s still the A axon with C axon extending onto it.
not due to a reduction of axons as if ablated the A axon instead of P then the G axon isn’t effected.

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16
Q

what is the labelled pathway hypothesis?

A

axons can selectively fasciculate with other axons, axonal surfaces carry labels or cues which different axon growth cones express different sets of receptors for the cues.

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17
Q

what do early axons (pioneer) do?

A

the form an axon scaffold on which later axons (followers) can extend.

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18
Q

what’s an example of axon scaffolds in vertebrates?

A

the subplate neurons in the mammalian cortex.

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19
Q

where do subplate neurons project prior to innervation of the cortex by the LGN (lateral geniculate nucleus) neurons?
what happnes if part of the subplate is ablated early on before the axons extend?

A

the subplate neurons project from the cortex to the thalamus.
if ablated before the axons extend the LGN innervation fails in the ablated region.

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20
Q

how to the pioneer axons find their way?

A

although it’s an apparently featureless environment, the pathways of pioneer axons are also stereotyped and growth cones appear to react at specific points in the pathway.

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21
Q

describe the pioneers pathways in the grasshopper embryo limb

A

the pioneer Ti1(tibial1) growth cone makes a specific turn at the limb boundry, and then again as it approaches the Cx1 cell.

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22
Q

what happens to the Ti1 pathway is Cx1 is ablated?

A

Ti1 growth cone stalls at the other side of the limb boundry

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23
Q

what are cells like Cx1 reffered to as?

A

stepping stones or guidepost cells

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24
Q

what does patterning information in the early embryo predict?

A

it predicts where axon tracts will form

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25
what do forebrain axons follow? what do hindbrain axons follow? what do spinal cord axons follow?
forebrain axons follow boundaries of domains of patterning gene expression the hindbrain axons follow the boundried of rhombomeres the spinal cord axons are attracted to and follow boundaries of the floor plate.
26
where are axon guidance cues located?
in axons and many other cell types in the early embryo.
27
how have experiments suggested that guidance cues can be both positive and negative?
cell ablations lead to growth cone stalls - this is as if an attractive force has been lost. Ti1 growth cone seems to avoid the limb boundry as if it were inhibitory
28
what are the 4 different ways in which guidance cues act?
contract attraction contraction repulsion chemoattraction chemorepulsion
29
what are lamella made up of? are these stuck down?
they are made up of F-actin. the actin bundles are crosslinked into a net. No they are highly motile.
30
what are filopedia made up of? are these stuck down?
F- actin, the actin bundles are polarised to form larger bundles. No they are highly motile.
31
what are growth cones made up of?
growth cone made up of F-actin and microtubules.
32
what happens to F-actin in a resting growth cone? what is sporadically dragged into the filopodia? what happens when the cone comes into contact with an attractive cue?
F- actin treadmills in the resting growth cone. in the resting growth cones, tubulin is dragged sporadically into the filopodia. this happens much more dramatically when the growth cone comes into contact with an attractive cue.
33
what happens when the growth cone comes into contact with an attractive cue?
F-actintreadmilling slowsand F-actin accumulates. the F-actin accumulation stabalises the filapodium and drags the microtubules into the back of the filopodium. this means that growth cones don't turn, they reorganise.
34
which part(s) of the growth cone is attached to the substrate?
the palm of the growth cone (the central domain) is attached. the filipodium aren't necessarily attached.
35
when a growth promoting cue is encountered, what two components lead to filopodial extension and reorientation of microtubules?
1. Molecular clutch is engaged and rearward actin treadmilling slows. resulting in forward movement of filopodium. 2. An Actomyosin-based actin-tubulin link pulls microtubules into the wake of extending filopodium.
36
Why is a stimulus of cue needed for forward movement?
this is needed to drive forward movement because attachment isn't enough to rearrange the cytoskeleton.
37
how was it discovered that growth cones can be repelled as well as attracted?
mixtures of neurons in culture were found to fasciculate only with their own kind, this wasn't due to attraction as when watched could see that the neurons were repulsed by each others axons Contact with each other's axons led to growth cone collapse.
38
what does growth cone collapse do to F-actin?
it destabilised F-actin (the concentration of F-actin drops)
39
what are Semaphorins?
a family of inhibitory guidance cues
40
how were semaphorins identified?
biochemical purification of the factor from the retina that were responsible for causing the collapse of sensory axons.
41
what types of semaphorins are there?
``` membrane bounds (retinal axons) secreted (e.g Sema3A) ```
42
what can secreted/ soluble semaphorins cause?
can cause growth cones to turn as well as collapse.
43
what are the 4 forces of axon guidance?
contact attraction and repulsion | chemo attraction and repulsion
44
why isn't it as simple as growth cones grow where they attach?
because growth cones need substrates which are permissive for growth not merely where they can attach.
45
what is laminin and where is it localised?
a growth promoting ECM protein, localised in the optic nerve.
46
what does laminin do to axon growth?
laminin allows some axons to grow there. A blockade of receptors for Laminin slows retinal axon growth. Laminin is permissive for growth only within a specific conc range. however laminin doesn't direct axon growth, it's permissive but not instructive.
47
what is another name for permissive substrates?
Contact attractants
48
what are non-permissive substrates also called? | does this imply a lack of adhesion?
contact repellants. | no as they can still make contact as seen in growth cone collapse.
49
what is seen in mice lacking Sema3A?
the axons wonder into wrong territories.
50
what is axon guidance a balance between?
permissive and non permissive. | although non permissive factors can channel axon growth, the axons still depend on permissive factors to grow.
51
what are Ephrins?
non-permissive factors used in early patterning and to guide axons. they are contact repulsion factors. cell surface molecules detected by receptors called Ephs.
52
what kind of pattern do ephs and ephrins have in mammalian embryos?
remarkable reciprocal pattern of expression.
53
how do ephs and ephrins help compartmentalise the early embryo? what are they used for later in development?
they cause repulsion between cells. | later they are sued to keep axons out of specific areas.
54
which of the 4 forces of axon growth act over a short distance? which are over a long distance?
``` contact = short chemo = long ```
55
how do chemo attractants and repellents act?
act over a long distance to direct axons is particular directions.
56
why are the roof and floor plate relevant to axon guidance?
they are organisors that pattern the cell types of the spinal cord. these release diffusible chemoattractants.
57
what did biochemical purification of the floor plate lead to the discovery of?
Netrin. this is the diffusible chemoattractant released by the floorplate, this is expressed along the midline of vertebrates NS. it's a secreted protein similar to laminin that can associate with the ECM.
58
what are commisural axons repelled by?
Bone Morphogenetic Proteins (BMPs) that are expressed by the roof plate.
59
what are BMPs important in?
determining which types of neurons are specified in the spinal cord. play a role in patterning axon pathways later on in development.
60
What does purified BMP7 cause? | what do cells expressing BMP7 do?
purified BMP7 causes commissural growth cone collapse. | cells expressing BMP7 mimic the repulsion of the roof plate.
61
why can some comimisural axons reach the floor plate without nectrin?
Shh can acoount for some of this as it attracts some axons towards it
62
how does Cyclopamine effect some axons reaching the floor plate?
it blocks Shh signalling, but it doesn't block nectrin.
63
what other gene is required for Shh signalling?
Smo
64
what happens when Shh signalling is stopped?
some C axons don't reach the floor plate.
65
what roles do Shh and BMPs have?
1. they specify neural fate | 2. co-operate with Netrin to guide commisural axons.
66
what is Sema1 and what does blocking it's function cause? | what does the blocking of Sema 2 cause?
Sema1 is a short range cue. Blocking function leads to: 1. axons straying into the wrong areas. 2. disrupts Ti1 guidance in a way that suggests the gradient of Sema2 directs Ti1 growth crone towards the body.
67
what happens when axons reach intermediate targets (choice points)? how is this seen in C axons?
they "reprogramme" this is seen with C axons when they reach the midline, they lose responsiveness to netrins. they also become sensitive to repellants after crossing the floor plate.
68
what are Slits? where are they found?
Slits are inhibitory molecules in the floor plate, they are semaphorins and proteins. expressed in floor plate and ventral spinal cord, thus creating a channel through which C. Axons grow.
69
what do levels of slit receptor at the cell surface determine?
whether or not the axons can cross the midline.
70
what does the roundabout gene Robo encode?
a receptor for the inhibitory protein slit
71
where is robo usually expressed at high levels? | what's robo's expression like on comissural axons?
expressed at high levels on axons that don't cross the midline. initially low levels on C. Axons, after crossing the midline these then have high levels.
72
what happens in robo mutants (no Robo made)?
slit is no longer detected. | all axons go back and fourth over the midline forming roundabouts of axons.
73
where is Comm expressed?
expressed only in those neurons that normally cross the midline and is switched off after they cross.
74
what happens when Comm is missing?
Robo protein is expressed at high levels in cells that would normally cross the midline and which now extend their axons longitudinally.
75
what happens if comm's expression is forced in all neurons?
robo protein is lost every where resulting in a phenotype just like the robo mutants (axons back and forth over midline like roundabouts)
76
what does Comm encode? what does this prevent?
a trafficking protein, this prevents Robo protein from reaching the cell surface so that the growth cone cannot receive Slit inhibitory signals before crossing.
77
what is Robo1?
a vertabrate homologue that is expressed on C axons, however it is expressed both before and after crossing the midline.
78
what is Rig1? what happens if Rig1 is lost?
it is a robo like protein in vertebrates that is present in pre-crossing fibres and appears to block Robo1 signalling until the midline is crossed. If Rig1 is lost then the Caxons fail to reach the midline (floor plate)
79
what's the basic mechanism behind how axons stay on the axon scaffold and how they get off the scaffold when they reach their target? what does this involve?
Control of fasciculation. | This involves "homophillic" binding by cell adhesion molecules (CAMs)
80
What is FascilinII?
a cell adhesion molecule in insects
81
what can homophillic interactions cause? when can this become a problem?
can cause two cell surfaces to bind together. | problem if expressed in a cell that doesn't usually agere, it can cause aggregation.
82
what happens in FasII mutants? when lost and overexpressed?
when lost they have many defasaciculated axons in overexpression it leads to novel fasciculation, and also includes "by passing" of targets as the axons fail to defasciculate and can't get off the scaffold.
83
what can FasII and other CAMs be regulated by?
expression of other proteins such as BEAT, that interfere with CAM-mediated adhesion.
84
what are the two main types of target selection?
1. discrete targets | 2. topographic maps
85
in the grasshopper and drosophila what happens if specific target muscles are ablated? what does this suggest?
it leads to the failure of relevant motor axons to leave main motor trunk at appropriate branch points. This suggests that axons are "looking" for specific "labels" on their targets (discrete targets)
86
what are the muscle "address" labels?
insect muscles carry a diverse set of molecules.
87
where's Netrin expressed? what does the loss of Netrin cause? what does ectopic Netrin cause?
in specific muscles when Netrin lost, is like ablating the muscles; the axons wander and don't make synapse even though the muscle is there. with ectopic netrin axons end up innervating the wrong muscles.
88
where is Fas3 expressed? | what does ectopic expression lead to?
expressed in specific muscles and the motor axons that innervate them. ectopic expression leads to Fas3 expressing axons to innervate new targets.
89
how do neurons maintain topology?
neighboring neurons send axons to neighboring sites in their target tomaintain topology.
90
what are the two possibilities for how neurons send axons to neighboring sites, proposed by sperry.
1. each axon has a unique label complimentary to a unique label in the target. (number of different labels seems implausibly high) 2. co-ordinate system encoded by gradients of signalling molecules stamps a "latitude and longitude"onto cells of the target. this would be read by complimentary gradients of receptors.
91
what does a stripe assay show about cells from the posterior tectum?
shows that they make a non-permissive factor that repels temporal retinal axons.
92
why do the temporal retinal axons avoid a repellant factor inthe posterior stripes?
1. the activity is abolished by heat treatment of the posterior but not anterior membranes. 2. posterior membranes cause temporal growth cones to collapse in vitro.
93
what is the inhibitory factor in the posterior tectum? how is this expressed?
inhib factor is two Ephrins, as sperry predicted thy are expressed in a gradient from posterior to anterior.
94
where is the Eph receptor for Ephrins A2 and A5 expressed?
in the retina in a counter gradient from temporal to nasal.
95
what happens in mice where both Ephrin A2 and A5 are KO?
temporal neurons project their axons into the posterior tectum and the topographicmap is disordered.
96
how are non-permissive repelant factors used to form topographic maps?
used instructively - they can direct growth cones to specific places.

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