NEUROTROPHINS

Question 1

When do synapses form?

Answer 1

As target are reached.

Question 2

In the embryo, the size of the target correlates with what?

Answer 2

The amount of innervation.

Question 3

How was the correlation of size of target and innervation found experimentally?

Answer 3

Viktor Hamburger showed removal of a limb bud yielded less neruons and addition of a limb bud to an embryo yielded more embryos. This suggest that the target is providing trophic support to cells.

Question 4

What is the neurotrophic factor hypothesis?

Answer 4

1. Neurons are produced in excess of need and the excess is eliminated over time.
2. Neurotrophic factors emanate from ragets to promote survival according to tissue size.

Question 5

What kinds of cell death are there?

Answer 5

Apoptosis Necrosis

Question 6

There are two classes of apoptotic genes, what are they?

Answer 6

Anti apoptotic

Pro apoptotic

Question 7

What are the two classes of caspases?

Answer 7

Initiator caspase

Executioner caspase

Question 8

How was Nerve Growth Factor found?

Answer 8

Testing on sarcomas showed the presence of a diffusible growth factor.

Question 9

Describe the Campenot Chamber experiment and the results.

Answer 9

There is a cell in a chamber with and inner layer and outer layer. If NGF is in either the inner or outer layer, the cells survive. If there is no NGF then there is retraction.
This not only affects cell survival but also neurite survival.

Question 10

NGF binds to receptor, it is internatlised and transported to the soma by retrograde transport. What happens when NGF is only administered to the axons?

Answer 10

The DRG cell bodies take up NGF and its receptor TrkA.

Question 11

What family does NGF belong to and give examples of other members.

Answer 11

The neurotrophin family
BDNF
NT3
NT4/5

Question 12

What are the features of TrkA receptor?

Answer 12

It is a tyrosine kinase receptor therefore undergoes induced dimerisation, autophosphorylation.
Activates MAP kinase pathway and Akt Pathway.
Is a high affinity receptor for NGF.
When NGF bind to TrkA, apoptosis is inhibited.

Question 13

What is p75-NTR?

Answer 13

It is a low affinity receptor to which NGF can bind. It promotes cell death or cell survival dependent on the ligand bound.
The pro form of NGF or BDNF drives apoptosis.
The mature form of NGF and BDNF drive cell survival.

Question 14

The different neurotrophins bind to difference receptors and are required for survival of different neurons. What are the ligands and receptors?

Answer 14

NGF binds with TrkA
NT3 binds with TrkC
BDNF binds with TrkB
Pro NGF adn Pro BDNF bind with p75-NTR

All neurotrophin ligands bind to p75-NTR

Question 15

What is there a differential dependence between neuron types and neurotrophins. Dependency on different combinations of neurotrophins can also change with what?

Answer 15

Time

Question 16

What dependency do newly born neurons have initially?

Answer 16

None

Question 17

Other factors can be neurotrophic. What are these?

Answer 17

Neurotrophic factors in activate the same core pathways but can belong to different families such as Glial Derived Neurotrophic Factor
Macrophage Stimulating Protein
Ciliary Neurotrophic Factor

Question 18

Why does cell death have to occur in development?

Answer 18

Keeping the tissue size and innervation in proportion.
Removal of transient structures.
The pruning of initially exuberant growth is widespread to differentiate initially similar structures,

Question 19

Many features of pruning are shared with apoptosis. What are these?

Answer 19

Cell fragmentation
Clearing by phagocytosis
Caspase 6 involvement

Question 20

How does pruning occur?

Answer 20

Involves specific cytoskeletal destruction, blebbing and fragmentation. Caspase 6 has been seen at fragmentation sites. Caspase 6 activated by Amyloid Precursor Protein which is shed from axons after NGF deprivation, binding to Death Receptor 6.

Question 21

What does blockade of death receptor 6 prevent?

Answer 21

Prevents axons degeneration and activation of caspase 6.

Question 22

What does Death receptor 6 have in common with p75-NTR?

Answer 22

They both have a death domain which can directly initiate caspace mediated programmed cell death.

Question 23

What is the difference between Death receptor 6 and p75-NTR?

Answer 23

Death receptors require ligand binding to activate cell death.
p75-NTR initiates cell death in the absence of a ligand and so is called a dependence receptor.

Question 24

Targets influence neruonal survival through production of what?

Answer 24

Neurotrophic factors