18 - Adaptation in Axon Pathfinding

Question 1

What is the gradient of Sema3A?

Answer 1

High at the dendrites, low at the axons

Question 2

How does Sema3A get into the cortex to be detected by the neurons?

Answer 2

It is secreted by cells

Question 3

In terms of Sema3A, where do axons grow?

Answer 3

At lower concentrations of Sema3A (repellant)

Question 4

True or false: the importance of BDNF gradients has been confirmed

Answer 4

False: it has not been confirmed genetically

Question 5

True or false: the importance of Sema3A gradients has been confirmed

Answer 5

True: it is known to play an important role in axon growth

Question 6

If a petri dish has stripes of BDNF, where will the dendrites and axon be?

Answer 6

The dendrites will be away from the stripes, and the axon will be on the stripes

Question 7

If a petri dish has stripes of Sema3A, where will the dendrites and axons be?

Answer 7

The dendrites will be on the stripes, and the axon will be away from the stripes

Question 8

Why is a gradient of extracellular cues important?

Answer 8

There would be no reason to grow towards / away something (guided by concentration of factors)

Question 9

What would happen if there was a constant concentration of extracellular cues?

Answer 9

There would not be proper growth, since the cells would not be guided on where to go (based on gradients)

Question 10

What happens if Sema3A is overexpressed in cortical neurons?

Answer 10

The gradient will be abolished, which will impact neuron growth

Question 11

How can a molecule gradient be abolished?

Answer 11

Overexpression or deletion of the molecule

Question 12

What conclusion can be drawn from the fact that axon initiation starts polarization, and that there is only one axon?

Answer 12

The axon must send signals to inhibit the other neurites from becoming an axon

Question 13

What molecule acts as a negative crosstalk in cell polarization?

Answer 13

cGMP

Question 14

What is needed for the initial breaking of the symmetry?

Answer 14

A neurite achieves a threshold of signaling that leads to axon formation

Question 15

What does the axon do to other neurties?

Answer 15

It sends negative signals to prevent them from reaching the threshold signaling to become an axon

Question 16

What happens in neurites inhibited by the axon?

Answer 16

They undergo other signaling to become dendrites (prevent threshold signaling of becoming an axon)

Question 17

True or false: one neurite can communicate with other neurites

Answer 17

True: this leads to only one axon being generated

Question 18

What happens if cAMP is locally elevated in one neurite?

Answer 18

It is locally decreased in other neurites

Question 19

What drives axon and dendrite formation?

Answer 19

Separate signaling pathways that engage in negative communication

Question 20

Which molecules have opposing roles in regulating axon and dendrite formation?

Answer 20

cAMP and cGMP

Question 21

What properties does cGMP have?

Answer 21

Water soluble (intracellular)

Question 22

What does GC do?

Answer 22

Create cGMP from GTP

Question 23

What enzyme creates cGMP?

Answer 23

Guanylyl cyclase (GC)

Question 24

What enzyme breaks down cGMP?

Answer 24

A phosphodiesterase (PDE)

Question 25

Where are ACs found?

Answer 25

In the membrane (transmembrane)

Question 26

Where are GCs found?

Answer 26

In the membrane (transmembrane), or soluble (in the cytoplasm)

Question 27

What regulates AC?

Answer 27

G-proteins

Question 28

What regulates GC?

Answer 28

NO (nitric oxide)

Question 29

What does NO stand for?

Answer 29

Nitric oxide

Question 30

What is the major source of cGMP in the brain?

Answer 30

Soluble GC (sGC)

Question 31

What does sGC stand for?

Answer 31

Soluble guanylyl cyclase

Question 32

What are the possible downstream targets of cGMP?

Answer 32

PKG, ion channels, and cGMP-PDEs

Question 33

What does PKG stand for?

Answer 33

Protein kinase G

Question 34

What cellular events use cGMP?

Answer 34

Neuronal development, vascular smooth muscle relaxation, and vision

Question 35

True or false: cAMP and cGMP need to be modified to cross the cell membrane

Answer 35

True: they are highly water soluble, not lipid soluble

Question 36

True or false: NO needs to be modified to cross the cell membrane

Answer 36

False: it is uncharged and nonpolar, so it can easily pass through the cell membrane

Question 37

What are the characteristics of NO?

Answer 37

Small, uncharged, and nonpolar

Question 38

What enzyme produces NO?

Answer 38

NOS (nitric oxide synthase)

Question 39

What does NOS stand for?

Answer 39

Nitric oxide synthase

Question 40

What does NOS do?

Answer 40

Converts L-arginine into NO

Question 41

What is nNOS?

Answer 41

A neural specific NOS

Question 42

How stable is NO?

Answer 42

Very unstable (only active for a few seconds)

Question 43

What is the consequence of NO being highly unstable?

Answer 43

It is highly transient and leads to local effects

Question 44

What type of signaling would be ideal for NO?

Answer 44

Transient paracrine and autocrine signaling

Question 45

What is the downstream target of NO?

Answer 45

sGC

Question 46

What is the structure of sGC?

Answer 46

A heterodimer with a beta regulatory domain, and an alpha domain

Question 47

What is the structure of the regulatory domain of sGC?

Answer 47

A heme functional group (iron)

Question 48

What is the function of iron in sGC?

Answer 48

It acts as a high affinity binding site for NO

Question 49

What happens if no NO is bound to the regulatory domain of sGC?

Answer 49

It is inactivated (no cGMP is produced)

Question 50

True or false: NO can only bind to sGC at the iron

Answer 50

False: it has two modes of binding (high affinity and low affinity)

Question 51

When does NO bind to the high affinity binding site?

Answer 51

At low concentrations

Question 52

When does NO bind to the low affinity binding site?

Answer 52

At high concentrations

Question 53

Where is the high affinity binding site?

Answer 53

At the heme group

Question 54

What is the activity of sGC at low concentrations of NO?

Answer 54

Partial activation (only high affinity binding)

Question 55

What is the activity of sGC at high concentrations of NP?

Answer 55

Full activation (low affinity binding too)

Question 56

Why is sGC partially activated at low concentrations of NO?

Answer 56

Only binding at the high affinity binding site

Question 57

Why is sGC fully activated at high concentrations of NO?

Answer 57

There is also binding at the low affinity binding site

Question 58

What happens if cAMP is presented to a neuron?

Answer 58

The axon will grow in the cAMP, and the dendrites will grow outside of the cAMP

Question 59

What happens if cGMP is presented to a neuron?

Answer 59

The axon will grow outside of the cGMP, and the dendrites will grow in the cGMP

Question 60

How can the cAMP and cGMP pathway be arranged to antagonize each other?

Answer 60

1. They have opposite actions on common downstream targets | 2. Reciprocal regulation (through activation of PDEs)

Question 61

What molecule increases cGMP levels?

Answer 61

Sema3A

Question 62

What is the effect of LKB1 when forskolin and Sema3A are added?

Answer 62

Decreased phosphorylation

Question 63

Why is there decreased phosphorylation of LKB1 when forskolin and Sema3A are added?

Answer 63

The cGMP inhibits the cAMP pathway

Question 64

What is downstream of PKG?

Answer 64

Dendrite formation

Question 65

What are the levels of cyclic nucleotides in the axon?

Answer 65

High cAMP and low cGMP

Question 66

What are the levels of cyclic nucleotides in the dendrite?

Answer 66

High cGMP and low cAMP

Question 67

What happens if PKA is inhibited in a neurite?

Answer 67

It will most likely differentiate into an axon

Question 68

True or false: inhibiting PKA has the same phenotype as overexpressing cGMP

Answer 68

True: both lead to dendrite formation

Question 69

What determines whether a neurite will be an axon or a dendrite?

Answer 69

The relative ratio of determinants from the cAMP and cGMP pathway

Question 70

What is the significance of sGC having two modes of activation?

Answer 70

This creates a basal level of cGMP, which can be used in signaling

Question 71

True or false: biological processes are usually at zero

Answer 71

False: they usually have a low, basal condition

Question 72

What determines the attraction and repulsion of the axon in axonal pathfinding?

Answer 72

The cAMP/cGMP ratio

Question 73

When the cAMP/cGMP ratio is high, what is the phenotype of the axon?

Answer 73

Attraction (turn towards it)

Question 74

When the cAMP/cGMP ratio is low, what is the phenotype of the axon?

Answer 74

Repulsion (turns away from it)

Question 75

How do guidance cues mediate axon pathfinding?

Answer 75

They regulate the cAMP/cGMP ratio

Question 76

What does a positive cue do to the neuron (intracellularly)?

Answer 76

Increases the levels of cAMP

Question 77

What does a negative cue do to the neuron (intracellularly)?

Answer 77

Increases the levels of cGMP

Question 78

What happens if PKA is inhibited and netrin is presented to the axon?

Answer 78

It will shift away from netrin