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BIO 317 > 19 - Keeping Neurons Alive: Neurotrophin Signaling > Flashcards

19 - Keeping Neurons Alive: Neurotrophin Signaling Flashcards

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1
Q

What discovery led to Rita Levi-Montalcini receiving the Nobel Prize?

A

The discovery of NGF

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2
Q

What type of molecule is a trophic factor?

A

A small protein or proteins

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3
Q

True or false: trophic factors are secreted by a few select cells

A

False: they are secreted by multiple cell types

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4
Q

How are trophic factors secreted?

A

As an inactive precursor

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5
Q

How are the precursors of trophic factors activated?

A

Through cleavage or fragmentation

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6
Q

True or false: precursors of trophic factors are inactive

A

False: they also have functions (although they are different that the functional trophic factor)

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7
Q

How are trophic factors transported?

A

Through the blood and lymph systems

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8
Q

What do growth factors do?

A

Stimulate cells to divide or increase in size

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9
Q

What is hyperplasia?

A

Stimulating cells to divide

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10
Q

What is hypertrophy?

A

Simulating cells to increase in size

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11
Q

What are the effects of trophic factors?

A

Cell differentiation, survival, expression of a particular cellular phenotype, and cellular morphological plasticity

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12
Q

True or false: a growth factor can act as a trophic factor

A

True: some can act as both

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13
Q

True or false: a trophic factor can act as a growth factor

A

True: some can act as both

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14
Q

True or false: growth factors can have the same functions in vivo vs. in vitro

A

False: they can have different functions

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15
Q

What are the functions of growth factors in vitro?

A

Proliferation, differentiation, chemo-attraction, cell death, and cell migration

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16
Q

What are the functions of growth factors in vivo?

A

Early development, tissue differentiation, wound healing and tissue repair, immune responses, and mediating sex/other hormones

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17
Q

How can differences arise between the functions of the same growth factor?

A

Based on the study (cell culture vs intact organism) and scale

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18
Q

What are neurotrophins?

A

A family of proteins essential for the development of the vertebrate nervous system

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19
Q

What are some examples of neurotrophins?

A

NGF, BDNF, NT3

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20
Q

What does NGF stand for?

A

Nerve growth factor

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21
Q

Which cells produce neurotrophins?

A

All cells of the nervous system (neurons, glial cells), ependymal cells, blood vessel endothelial cells, and cells from innervated tissues (muscle, epidermis, etc.)

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22
Q

What are some examples of glial cells?

A

Astrocytes and oligodendrocytes

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23
Q

True or false: neurotrophic factors come from a specific region in the body

A

False: they come from all over the body

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24
Q

When was Victor Hamburger’s work done?

A

1930s

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25
Q

What experiments did Victor Hamburger do?

A

He added or removed limb buds to see how this affected neuron growth and development

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26
Q

What were the results of Hamburger’s experiments?

A

Less neurons grew when the limb buds were removed, and more neurons grew when an extra limb bud was added

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27
Q

What was the conclusion of Hamburger’s experiments?

A

The peripheral tissue was sending signals for the neurons to grow and divide

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28
Q

How did Rita’s hypothesis differ from Hamburger’s hypothesis?

A

Rita believed that there was a degenerative process, while Hamburger believed there was a failure of differentiation

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29
Q

What evidence did Rita find for her hypothesis in the 1940s?

A

Neurons regularly underwent apoptosis during development

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30
Q

According to Rita’s hypothesis, what happened when a limb bud was removed from the embryo?

A

There was increased cell death

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31
Q

According to Hamburger’s hypothesis, what happened when a limb bud was removed from the embryo?

A

There was decreased cell growth / proliferation

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32
Q

What was Rita’s hypothesis regarding nerve development?

A

Feedback signals required for neuronal survival are in limited supply

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33
Q

In development, which neurons will survive?

A

The ones that take up enough neurotrophic factor

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34
Q

What is meant by a “matching” of target area?

A

The target cells will produce enough neurotrophic factors to match the number of target cells

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35
Q

True or false: neurotrophic factors are only important in development

A

False: they are also important after development

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36
Q

How are neurotrophic factors used after development?

A

Axonal processes can compete for neurotrophic factors

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37
Q

What determines whether a neuron will take up significant neurotrophic factor?

A

How active the synapse is

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38
Q

What alters how active a synapse is (for taking up neurotrophic factors)?

A

Experience and stimulation

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39
Q

What happens to neuronal development when the chick embryo was paralyzed?

A

Only some of the neurons survived

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40
Q

What was the conclusion of the experiments involving paralyzing the chick embryo?

A

The neuron and muscle together determine how the muscle signals to the neuron (regarding neurotrophic factors)

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41
Q

What is an important regulator of neurotrophic factor release?

A

Muscle activity

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42
Q

What experiments did Rita perform in the 1950s?

A

Transplanted tumors induced potent growth of the nervous system in chick embryos

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43
Q

What was the conclusion of Rita’s experiments in the 1950s?

A

The tumor released a nerve growth-promoting factor that acted on the nerves (trophic growth factor hypothesis)

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44
Q

What is the significance of tumors not needing direct contact in Rita’s experiments (in the 1950s)?

A

There must have been a secreted factor (trophic growth factor hypothesis)

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45
Q

What was the advantage of using sarcoma tissue?

A

There was more material to work with

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46
Q

Who was Stanley Cohen?

A

A biochemist hired to help purify NGF

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47
Q

Why was Stanley Cohen hired to the Hamburger lab?

A

They needed a biochemist to help purify NGF

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48
Q

What was in the compounds of the extract that Cohen purified?

A

Proteins and nucleic acids

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49
Q

What did Cohen do to determine if NGF was the protein or nucleic acid?

A

Added snake venom to inactivate the nucleic acids

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50
Q

Why was snake venom used to determine if NGF was a protein or nucleic acid?

A

Snake venom has nucleic-acid degrading enzymes

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51
Q

What was the problem with using snake venom?

A

It contained more nerve growth-promoting activity than the tumor itself

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52
Q

Besides snake venom, what is a rich source of NGF?

A

Mouse salivary glands

53
Q

True or false: NGF is a potent molecule

A

True: it can lead to rapid changes with a small concentration

54
Q

What was needed to study and purify NGF?

A

A rapid assay (faster than adding sarcoma pieces to embryo)

55
Q

How come a rapid assay was needed to study NGF?

A

Extracting proteins can degrade quickly and cannot be measured

56
Q

What was the rapid assay used to identify NGF?

A

Root dorsal ganglion cells from chicken embryos

57
Q

Besides NGF, what did Cohen find in the NGF extracts?

A

EGF

58
Q

What does EGF stand for?

A

Epidermal growth factor

59
Q

What was the effect of EGF on mice?

A

Teeth erupted, and eyelids opened sooner than normal

60
Q

True or false: EGF can only affect epidermal cells

A

False: it could also affect other types of cells

61
Q

What was the conclusion regarding EGF acting on multiple types of cells?

A

Any cell that has an EGF receptor can respond to EGF

62
Q

What did Cohen discover about the EGF receptor?

A

EGF and the EGF receptor, when bound together, entered the cell

63
Q

What is the structure of NGF?

A

Dimeric, with binding along a hydrophobic interface

64
Q

How did Rita and Cohen prove that NGF was the intended factor?

A

By using anti-NGF antibodies to neutralize it

65
Q

How could NGF be verified using modern technology?

A

By using a knockout mice

66
Q

What happened when NGF was blocked by an antibody?

A

There was no peripheral ganglia

67
Q

What are PC12 cells?

A

A neuron-like cell line from a rat tumor

68
Q

Without NGF, how do PC12 cells grow?

A

Similar to tumors

69
Q

With NGF, how do PC12 cells grow?

A

Similar to neurons

70
Q

What was the conclusion regarding adding NGF to PC12 cells?

A

NGF stimulates neuronal phenotypes separate from the prevention of cell death

71
Q

According to the PC12 model, what neural phenotypes can be gained upon addition of NGF?

A

Neurites, sodium action potential, stop cell division, synthesize neurotransmitters, and create neuronal specific proteins

72
Q

Why is it difficult to study NGF in vivo?

A

Neurons die when NGF is knocked out

73
Q

What was done to get around the difficulty of studying NGF in vivo?

A

BAX was knocked out to inhibit cell death

74
Q

What is BAX?

A

A gene involved in mitochondrial death and apoptosis

75
Q

What happened when both NGF and BAX were knocked out?

A

The cell survived, but could not differentiate into a neuron (based on the NGF functions)

76
Q

What happened when NGF was knocked out?

A

The cell died (no survival)

77
Q

True or false: NGF has branched effects

A

True: it can lead to multiple phenotypes

78
Q

What are the branched effects of NGF?

A

Control neuronal phenotype, and prevent cell apoptosis

79
Q

What was done to study the signaling pathways of NGF?

A

Study the known signaling pathways in PC12 cells

80
Q

In PC12 cells, what was added that mimic the addition of NGF?

A

Addition of constitutively active Ras protein

81
Q

What happens when anti-ras was added to PC12 cells?

A

They did not get the neuronal phenotype

82
Q

What was the control in experiments with anti-ras and PC12 cells?

A

Another antibody (anti-something else)

83
Q

What was the purpose of the control in the experiments with anti-ras and PC12 cells?

A

Demonstrate that adding the antibody would not change the system (had to be anti-ras)

84
Q

What was the conclusion of the studies with anti-ras in PC12 cells?

A

NGF uses a proto-oncoprotein pathway for neuronal survival and development

85
Q

What is TrkA?

A

The receptor tyrosine kinase for NGF

86
Q

What receptor binds to NGF?

A

TrkA

87
Q

What happens to TrkA when NGF binds to it?

A

It dimerizes and leads to autophosphorylation of the RTK

88
Q

What pathways are activated by TrkA?

A

The PI3K, ras, and PLC pathway

89
Q

What does the PI3K pathway lead to?

A

The activation of Akt

90
Q

What does the Ras pathway lead to?

A

The activation of the MAP kinases

91
Q

What does the PLC pathway lead to?

A

The activation of intracellular calcium and PKC

92
Q

True or false: TrkA is a proto-oncogene

A

True: it can lead to constant activation of the Ras pathway if mutated

93
Q

What is the structure of the TrkA oncoprotein?

A

It is fused with tropomyosin, which keeps it constitutively dimerized and active

94
Q

What happened when the constitutively active TrkA receptor was put into non-neuronal cells?

A

It led to uncontrolled mitogenesis

95
Q

What happened when the constitutively active TrkA receptor was put into neuronal cells?

A

It mimicked NGF action

96
Q

How are the different Trk isoforms formed?

A

Through alternative splicing

97
Q

What is the significance of alternative splicing in Trk receptors?

A

It leads to different isoforms, which alters the downstream signaling pathways

98
Q

True or false: RTKs have similar extracellular domains

A

False: the extracellular domains are fairly diverse

99
Q

True or false: RTKs have similar intracellular domains

A

True: the intracellular domains are fairly similar

100
Q

What is the preferred ligand for TrkA?

A

NGF

101
Q

What is the preferred ligand for TrkB?

A

BDNF and NT-4

102
Q

What is the preferred ligand for TrkC?

A

NT-3

103
Q

What is a preferred ligand?

A

A ligand that binds with high affinity to the receptor

104
Q

What is a non-preferred ligand?

A

A ligand that binds with low affinity to the receptor

105
Q

What is a non-ligand?

A

A ligand that does not bind to the receptor

106
Q

Besides Trk receptors, what receptors can NGF bind to?

A

p75NTR

107
Q

What does p75NTR stand for?

A

p75 neurotrophic receptor

108
Q

How does p75NTR interact with Trk receptors?

A

p75NTR can interact positively or negatively with Trk

109
Q

True or false: Trk can only transmit positive signals

A

True: it causes the cell the survive

110
Q

True or false: p75NTR can only transmit positive signals

A

False: it can also send negative signals, such as promoting apoptosis

111
Q

True or false: Trk can only bind to mature NGF

A

True: NGF needs to be cleaved to bind to Trk

112
Q

True or false: p75NTR can only bind to mature NGF

A

False: it can also bind to pro-NGF

113
Q

When pro-NGF is bound to p75NTR, what signal is transmitted?

A

A negative signal

114
Q

When NGF is bound to p75NTR, what signal is transmitted?

A

A positive signal

115
Q

Besides pro-NGF, what binds to p75NTR to promote a negative signal?

A

Sortilin

116
Q

What does sortilin do?

A

It promotes a negative pathway when bound to p75NTR

117
Q

Which receptor does pro-NGF have a higher affinity for?

A

p75NTR

118
Q

Which receptor does NGF have a higher affinity for?

A

TrkA

119
Q

True or false: p75NTR can bind to all classes of neurotrophins

A

True: it can bind to all neurotrophins in a mature or pro form

120
Q

True or false: p75NTR only has preferred ligands

A

True: it has no non-preferred ligands or non-ligands

121
Q

In terms of neurotrophic receptors, what is important for determining the number of surviving cells?

A

The ratio of Trk and p75 receptors

122
Q

True or false: p75 plus Trk can lead to greater cell survival than just Trk

A

True: this combination of effects leads to an overall greater effect

123
Q

How is the ratio of Trk to p75 seen in muscle contraction?

A

Motor neuron axons can retract with pro-BDNF, and extend with BDNF (through their receptors)

124
Q

What is the importance of motor neuron axons retracting and extending?

A

It stabilizes or destabilizes the synapse at the neuromuscular junction

125
Q

True or false: BDNF is a candidate for a therapeutic agent in Parkinson’s

A

True: it has been shown to promote neuroprotection and neuroregeneration

126
Q

What was found to be neuroprotective in Parkinson’s patients?

A

Physical training

127
Q

What mediates physical training being protective in Parkinson’s disease?

A

BDNF and TrkB

128
Q

How is p75 seen in HIV?

A

There is an increase in p75, leading to increased cell death, and impaired cognitive function

129
Q

What is different about neurons (compared to other cell types) that leads to the different phenotypes observed?

A

Different combinations of signaling compartments (pathways) to act on

BIO 317 (27 decks)

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