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Intercal - Advanced molecules, membranes and cells > Axon Guidance 1 > Flashcards

Axon Guidance 1 Flashcards

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Organic Chemistry 101 flashcards
1
Q

What are growth cones?

A

the sensory organelles of growing axons

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2
Q

What is the role of the growth cone

A

they translate extracellular information into cellular responses.

has lots of cell surface receptors which instigate a variety of transducer signals that ultimately impinge on the cytoskeletal machinery of the growth cone.

this is where axon microtubules are stabilised or destabilised.

These axon tubules respond to interactions with actin→the filamentous proteins of the growth cone extremity.

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3
Q

What are the three regions of growth cones

A

Peripheral region - lamellipodia
Transitional region - between both
Central region - central organelles and microtubules

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4
Q

What are the lamellipodia

A

Outgrowth of growth cone that is made up of actin

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5
Q

What are the filopodia

A

Dynamic assemblies of filamentous F-actin (finger like projections at periphery) (occurs through polarised filaments)

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6
Q

What is axon pathfinding

A

The key to axon pathfinding is the dynamic nature of the axon cytoskeleton. To change direction an axon must be able to rapidly dismantle its cytoskeleton in one orientation in favour of its establishment in another direction. A nerve process has a backbone of filamentous protein polymerised together to form tensile cables, commonly known as microtubules or intermediate filaments.

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7
Q

What interacts with filopodia to stabilise them

A

Microtubules - stabilises them and prevents them from retracting

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8
Q

What do the microtubules become

A

Highly stabilized in the central region leading to neurite formation

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9
Q

What is the role of actin in the cytoskeleton

A

Actin monomers can exist as free monomers or diffuse networks of polymerised actin filaments.

They can also be polarised to form rigid filaments that form the backbones of thin processes that protrude from the growth cone body. These are filopodia.

Often, between filopodia veils of cytoplasm (lamellipodia) extend, largely made up of meshes of actin filaments and diffuse actin.

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10
Q

What 4 steps of axon guidance are needed

A

Neurite initiation
Axon growth and pathfinding
Axon termination
Survival in target tissues

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11
Q

How does neurite initiation work

A

Actin filaments are distributed evenly around the microtubule rich cell body –> actin localised to tips and microtubules at the backbone of the neurites –> one neurite preferred and becomes axon, the rest resorb into the body or become dendrites

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12
Q

How do actin filaments develop?

A

Under steady-state conditions, ATP-actin binding occurs and is added to the distal end of an actin filament

ATP –> ADP and the iP leaves and becomes ADP-actin

ADP-actin is released from the proximal end

ATP-actin and release of ADP-actin occurs at the same rate meaning no change in filament length (treadmilling)(same added to distal as is getting removed from proximal end)

if more is added to wrong side- will start to rectract.

The equilibrium between actin polymerisation and depolymerisation is the driving force behind axon elongation and retraction.

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13
Q

How do microtubules develop

A

Similar to actin filaments, undergo subunit turnover but with alpha/GTP-beta tubulin dimers.
These tubulin dimers are added to the distal end and alpha/GDP-beta is removed at the proximal end

Post-translational tubulin modification (detyrosination or acetylation) ages and stabilises the microtubule

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14
Q

What is ADF cofilin recycling

A

It severs actin filaments and aids dissociation of ADP-actin

Once ADP-actin is detached, it dissociates from ADP-Actin

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15
Q

When does ADF/cofilin become inactivated

A

Phosphorylation by LIM kinases and then stabilised by 14-3-3zeta proteins

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16
Q

How is ADF-cofilin reactivated

A

Phosphatases through the PIP3 receptor

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17
Q

What are Rho GTPases

A

Cytoskeletal regulating molecules

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18
Q

What is the Rho function, part of the Rho family

A

A disruptive cytoskeletal regulating molecule that breaks up the actin filaments

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19
Q

What is the Rac function, part of the Rho family

A

Promotes lamellipodia outgrowth

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20
Q

What is CDC42’s function, part of the Rho family

A

Promotes filopodial outgrowth

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21
Q

What activates RhoGTPases

A

Specific GEF’s - guanine nucleotide exchange factors which promote filopodia growth through phosphorylation of Rho-GDP to Rho-GTP

22
Q

What do GEFs and GAFs do overall

A

Regulate the cytoskeleton

23
Q

What is rho GTPases inactivated by

A

GAPs - GTPase activating proteins They de-phosphorylate Rho GTP and inactivate it

24
Q

What 3 mechanisms are in play to regulate growth cone development

A

Chemical

Physical

Electrical

25
Q

Give some degradation examples by Rho GTPase on the cytoskeleton

A

Myosin promotes retrograde flow of the actin filament and thus prevents elongation

Rho blocks MLC phosphatase, having the net effect of stimulating myosin and therefore prevents elongation

Cofilin disassembles ADP actin

26
Q

Give some examples where Rho GTPases promote axon growth

A

Scar and N-WASP promote filament branching

VASP family and profiling prevent capping of actin filaments which promotes more monomer binding

Rac also inhibits the effects of capping proteins that prevent addition of actin to distal ends

27
Q

What are the 3 stages of axon elongation

A

Protrusion -filopodia move forward

Engorgement - organelles follow filopodia

Consolidation - microtubules become stabilised by post-translational modification and a new membrane is formed around the axon

28
Q

How does chemical axon guidance work

A

Involves chemotropism - through attraction and repulsion

29
Q

What is chemotropism and how does it work

A

Chemotropism involves the biased expression of molecules in a growth cone’s vicinity that influences the turning of that growth cone in one direction or another.

Such cues might be discrete, in that a given molecule or protein is detected on one side of the growth cone and not the other, or they might be laid down in gradients, such that a growth cone can detect on which side a given signal is stronger, and therefore can decide whether to turn towards (chemoattraction) or away (chemorepulsion) from the source.

30
Q

How do guidepost cells regulate axon guidance

A

Physical axon guidance relies on axonal contact with structures en route to its target cell. These may take the form of individual intermediate cells in the axon’s pathway, or groups of cells or cellular processes that effectively form tram lines for the axon to grow along. Physical cues would also include extracellular matrix structures that are generally permissive for axon growth.

31
Q

Give an example of physical guidepost axon guidance

A

Guide post cells in grasshopper embryos -

In the femur, til cells contact with an intermediate pre-axonogenic neuron to keep it on course.

When this neuron interacts with the trochanter-coxa boundary, it turns 90 degrees and continues growing

A further turn is seen at the coxa region

32
Q

What are the three types of physical axon guidance

A

Discrete guidance cells (pre-axonogenic neurons)

Intermediate guiding cells also support some outgrowth with their own short processes which the neuron supports itself on

Continuous chains of cells such as epithelial cells.

33
Q

What promotes physical axon guidance

A

The molecular requirements for physical growth support involve a relatively uniform permissive substrate for axons to grow on, such as laminin, fibronectin or collagen laid down in matrix or fibre-like structures, or cell adhesion molecules such as NCAM, L1 or axonin-1.

34
Q

What inhibits physical axon guidance

A

physical cues may also be inhibitory, since contact with cells that express inhibitory ligands such as membrane-bound semaphorin or myelin proteins such as Nogo prevent axon growth and may induce branching or a change in direction. Such growth or growth inhibition is contact-mediated, and therefore requires physical contact with the cells or structures expressing the permissive or inhibitory molecules.

35
Q

Why can electrical axon guidance work

A

Becomes electric fields can be detected across the whole embryo and within specific regions.

Different current flows occur as a result of different tissues possessing different resistance/thicknesses.

36
Q

Why is electrical axon guidance controversial

A

Because scientists believe it manipulates the process too much to be a natural phenomenon.

37
Q

Does electrical axon guidance actually work

A

Yes, go towards negative electrode in vitro.

Can definitely manipulate it, whether it’s involved originally or not it is hard to say.

38
Q

What 2 mechanisms may underpin electrical axon guidance

A

Asymmetrical protein distribution - charged receptor proteins orientate themselves with one side of the growth cone and react with growth factors with that side of the growth cone and grow outwards towards it.

Key signalling molecules from the cytoplasm are distributed in gradients towards the cathode.

39
Q

Give an example of key signalling molecules from the cytoplasm moving towards the cathode.

A

GFP-labelled Akt moves towards the negative electrode in epithelial cells.

40
Q

Why do we grow more axons than what is needed

A

as a good way of ensuring that all necessary contacts are made with target tissues and cells, rather than relying on the exact number of axons to project without error.

41
Q

What are the TrK signalling mechanisms used for

A

Many Axons grow however not all will survive. There is only a certain amount of growth factor present and once it reaches its destination some axons will die off to save excess materials for other more important areas.

42
Q

How does TrK signalling mechanisms work

A

NGF (nerve growth factor) binds to tyrosine receptor kinase (TrK) when NGF binds the whole ligand-receptor complex is endocytosed into the cell and it transports back to the cell body and this promotes cell survival.

43
Q

What is the domino model

A

TrK binds to the growth cone leading to a ligand-independent propagation of TRK phosphorylation back to the cell to turn on signalling molecules to enter the nucleus and turn on genes for cell survival.

44
Q

What is the retrograde effector model

A

Messenger molecules activated in the growth cone may be transported back to the nucleus to turn on genes for cell survival

45
Q

What other method is used to promote neuron survival other than the TrK signalling mechanisms

A

Synaptic connectivity and electrical activity of the neurons is initiated - promotes neuronal survival

46
Q

What is the role of F-actin

Wider reading

A

F-actin retrograde flow, driven by myosin II contractility in the transition (T)-zone and F-actin bundle treadmilling, keeps the growth cone engine idling and responsive to directional cues. Growth cone receptor binding to an adhesive substrate leads to the formation of a complex that acts like a molecular `clutch’ mechanically coupling receptors and F-actin to stop retrograde flow and driving actin-based forward growth cone protrusion.

47
Q

What mediates axon growth inhibition

Wider reading

A

RTN4R - Nogo receptor 1

48
Q

What was seen during p75 knockout

Wider reading - wang et al

A

Outgrowth inhibition was absent

49
Q

What is cethrin treatment and how does it work

WIDER READING - Baptistie - 2006

A

Used for neurite growth by applying to the site of nerve injury.

Works by inhibiting ROCK, which is known to phosphorylate proteins that inhibit neurite outgrowth.

50
Q

What role does the NgR (Nogo-66 receptor) have in mice brains

WIDER READING - Mcgee 2005

A

It limits visual cortex plasticity - mutant mice with non-functional NgR resulted in enhancement of visual cortex plasticity after the critical period into adulthood, such that adult plasticity in the mutant mice resembled normal visual plasticity in juvenile mice brains

This is being researched as a possible treatment for amblyopia (lazy eye)

Intercal - Advanced molecules, membranes and cells (31 decks)

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