Lecture 4 - Neuronal Survival and Growth

Question 1

Is the neurotransmitter phenotype of a neuron plastic?

Answer 1

-yes in the PNS but they are more so hardwired in the CNS
-the neurotransmitter phenotype of a neuron is plastic in the PNS things are much more plastic and malleable even in regards to injury while the CNS is more hardwired; early on in development right when it is told it is neuron it is told the neurotransmitter it is going to be while in the periphery can change based on target; the in the CNS when driven form subventricular zone you know what neurotransmitter it is going to be; this phenomenon is def during development - during injury disease maturation and cell death glia change and the neurons themselves can be coaxed into changing and it is much less apparent after development

Question 2

The type of neurotransmitter released by a neuron can be decided by tf programs or cell fate, but what else can influence transmitter identity?

Answer 2

nature of the target

Question 3

Can the transmitter identity of a neuron change after the early development?

Answer 3

yes as a result of rewiring and connectivity

Question 4

What two types of neurons do neural crest cells differentiate into?

Answer 4

sympathetic and sensory neurons

Question 5

If a neural crest cell becomes a sensory neuron precursor what path does it follow?

Answer 5

sensory precursor—>sensory neuron—->nociceptive or proprioceptive neuron

Question 6

If a neural crest cell becomes a sympathetic neuron precursor what path does it follow?

Answer 6

sympathetic neuron precursor—>sympathetic neuron—->default is noradrenergic neurons but if exposed to target-derived gp130 cytokine will become a cholinergic neuron

Question 7

What of sympathetic neurons determines neurotransmitter phenotype?

Answer 7

the target

Question 8

What are sympathetic neurons initially specified as?

Answer 8

having the noradrenergic transmitter phenotype

Question 9

How is the sympathetic neuron neurotransmitter identity plastic?

Answer 9

-it can synapse onto a muscle cell and the presynaptic terminal has a dense core vesicle because they are neurotransmitter peptides so most of these cells before they migrate from the neural crest become these neurons
-secretion of signals from gland cells targets IL-6 cytokine have a potent transformative effect to direct cholinergic fate and the signal; binds to the presynaptic terminal and goes retrogradely back to the nucleus and tuns off noradrenergic and turns on ACh and they are small clear vesicles packed with ACh

Question 10

What is the neurotransmitter phenotype of central neurons controlled by?

Answer 10

basic helix loop helix transcription factors
-neurogenin and MASH-1 are basix bHLH transcription factors expressed in neuroepithelial cells but not in mature neurons (in the cerebral cortex)

Question 11

What does neurogenin-1 and -2 encode?

Answer 11

glutamatergic neurons

Question 12

What does MASH-1 encode?

Answer 12

GABAergic neurons

Question 13

When is neurotransmitter fate in the CNS determined?

Answer 13

before neuronal differentiation, migration, and final specification; neurotransmitter identity in the CNS is more hardwired than in the periphery

Question 14

In the cerebellum what does the bHLH TF Math-1 encode?

Answer 14

Glutamatergic neurons

Question 15

In the cerebellum what does the bHLH TF Pft1a encode?

Answer 15

GABAergic neurons

Question 16

What do over half of all neurons born during development ultimately do?

Answer 16

die through a deliberate cell programmed death

Question 17

What does the survival of motor neurons depend on?

Answer 17

trophic signals provided by their muscle targets

Question 18

If you remove a limb bud from a chick embryo what happens?

Answer 18

-you get less motor neuron survival

Question 19

If you transplant a limb bud onto a chick embryo what happens?

Answer 19

-you get more motor neuron survival

Question 20

What are limb buds?

Answer 20

muscle tissue in the chick and look at the spinal cord and the MNs can manipulate the limb buds

Question 21

What does blocking muscle activity allow for?

Answer 21

the survival of more motor neurons

Question 22

What is curare?

Answer 22

a blocker of postsynaptic acetylcholine receptor in the muscle

Question 23

If you put curare why do you rescue MN that would otherwise not be rescued?

Answer 23

Drug doesn’t prevent synapse from being formed but prevents transmission; don’t allow synapse to function you essentially still die off and that is due to the fact the muscle contraction allow for the released of NGF in a specific area but when you prevent the muscle from depolarizing the target is not able to release NGF in a specific area for only like two neurons and rather releases NGF into a low level larger area of neurotrophin causing more neuronal survival

Question 24

What can we say about the role of the muscle and NMJ activity in controlling survival of MNs?

Answer 24

synaptic activity localized release of a signal from the muscle that may promote survival of some motor neurons but ultimately leads to cell death of at least 25% of all MNs’
-additional muscle tissue enables increased neuronal survival

Question 25

What is the neurotrophic factor hypothesis?

Answer 25

A small amount of a signal is released by synaptic targets and is necessary to inhibit the default program of cell death. competition by many neurons for the limiting amount of this signal determines which neurons live or die

-neurotrophins are secreted by a target and bind to receptors on the axon tip and this is internalized and sends a prosurvival signal back to the soma
-neurons that do not receive enough of this signal go through apoptosis

Question 26

What different neurotrophic factors promote the survival of distinct populations of DRG neurons?

Answer 26

BDNF, GDNF, NGF, NT-3,-4,-5
-the neurons only have receptors for certain subsets for the neurotrophins

Question 27

What receptor does NGF bind to?

Answer 27

Trk A and p75

Question 28

What receptor does BDNF bind to?

Answer 28

TrkB and p75

Question 29

What receptor does NT-3 bind to?

Answer 29

TrkC and p75

Question 30

What are the two main neurotrophin receptors?

Answer 30

trk receptors - survival and death
p75 - death and binds all Nts with low affinity so at low conc

Question 31

What is cell survival the result of?

Answer 31

an imbalance of anti-apoptotic and pro-apoptotic signals

Question 32

What does the binding of the nerve growth factor to the TrkA receptor activate?

Answer 32

alternate intracellular signaling pathways which can result in neuronal differentiation or neuronal survival

Question 33

What happens when NGF binds to TrkA?

Answer 33

-induces dimerization which trigger cross phosphorylation which leads to the recruitment of adaptor proteins and if FRS2 is expressed then the neuron will differentiate if it does not the neuron will survive

Question 34

If FRS2 is expressed in a neuron how does it promote differentiation?

Answer 34

through a Ras signaling system

Question 35

If FRS2 is not expressed in a neuron how does it promote survival?

Answer 35

through PI3-K

Question 36

What do neurotrophins suppress?

Answer 36

apoptosis

Question 37

What is the conserved set of proteases called which signal a coordinated destruction of cellular materials leading to an organized death of the cell?

Answer 37

caspase (also seen in c elegans)

Question 38

What are the two types of pathways which trigger cell death?

Answer 38

1. extrinsic pro death
2. intrinsic activation of mitochondrial pathway
   -which both activate caspase-3 and drive cell death

Question 39

How does binding of NGF to TrkA activate prevent cell death?

Answer 39

activates the PI3K signaling and inhibits caspase-9

Question 40

Summary

Answer 40