15 - Signaling Mechanisms Underlying Axon Guidance I

Question 1

What question can be asked regarding redundancy?

Answer 1

Do we have redundancy, or are some proteins critical for functioning

Question 2

True or false: there are neuropathologies associated with LKB1

Answer 2

False: there are no neuropathies associated with LKB1

Question 3

What is STRAD?

Answer 3

A cofactor for LKB1

Question 4

What is the cofactor of LKB1?

Answer 4

STRAD

Question 5

In basal conditions, where is LKB1 located?

Answer 5

In the nucleus

Question 6

In basal conditions, where is STRAD located?

Answer 6

In the cytoplasm and in the nucleus

Question 7

What do STRAD and MO25 do to LKB1?

Answer 7

1. Phosphorylate it at Ser431 to activate it

2. Localize LKB1 into the cytoplasm to function

Question 8

What would happen to a cell without STRAD?

Answer 8

LKB1 would be localized in the nucleus

Question 9

What functions does LKB1 have in the nucleus?

Answer 9

Unknown, but it cannot mediate its downstream targets for cell polarization

Question 10

True or false: there are neuropathologies associated with STRAD

Answer 10

True: PMSE is associated with a truncated STRAD gene

Question 11

What are the symptoms of PMSE?

Answer 11

Psychomotor disability, epilepsy, and early childhood mortality

Question 12

Why does PMSE lead to neuronal problems?

Answer 12

The truncated STRAD cannot localize LKB1 into the nucleus for proper axon formation

Question 13

How come there are no pathologies associated with LKB1?

Answer 13

It is a critical enzyme, and thus its deletion is lethal (embryonic death)

Question 14

How come there are pathologies associated with STRAD?

Answer 14

It is important, but not critical, for axon development, so people can still survive (other mechanisms)

Question 15

What happens to STRAD in PMSE?

Answer 15

It gets truncated

Question 16

What is the importance of crosstalk?

Answer 16

Regulation, specificity, redundancy, and amplification

Question 17

What are the components of a signaling pathway (for an intricate and regulated pathway)?

Answer 17

On/off processes with time delays

Question 18

What is a feed forward mechanism?

Answer 18

A signaling mechanism originates at one upstream regulator, and converges on one function

Question 19

True or false: for a feed forward mechanism, the paths must be the same

Answer 19

False: the paths (signaling determinants) can be different, but the start and end points have to be the same

Question 20

True or false: for a feed forward mechanism, the start and end points must be the same

Answer 20

True: the paths (signaling determinants) can be different, but the start and end points have to be the same

Question 21

What is the advantage of a feed forward mechanism?

Answer 21

It is a relentless signaling to activate a critical function

Question 22

True or false: the paths in a feed forward mechanism must converge at the same time

Answer 22

False: there can be time delays between the different paths, as long as they converge on the same function

Question 23

What is the difference between a feedback and a feed forward?

Answer 23

A feedback loops back onto an upstream regulator, while a feed forward moves forward towards a downstream function

Question 24

What is coupled to a positive feed forward mechanism?

Answer 24

Negative regulation (with a time delay)

Question 25

What is coherent feed forward?

Answer 25

When the two branches have the overall same sign

Question 26

What is incoherent feed forward?

Answer 26

When the two branches have the opposite signs overall

Question 27

True or false: a coherent feed forward can be positive or negative

Answer 27

True: as long as the overall messages of each branch are the same, it is a coherent feed forward

Question 28

True or false: a positive coherent feed forward can only have positive linkages

Answer 28

False: only the overall message of the branch needs to be positive (A --| B --| C = A --> C)

Question 29

True or false: a negative coherent feed forward can only have negative linkages

Answer 29

False: only the overall message of the branch needs to be negative (A --> B --| C = A --| C)

Question 30

True or false: a coherent feed forward must have the same linkages

Answer 30

False: they only need to communicate the same overall message (A --| B --| C = A --> C)

Question 31

True or false: an incoherent feed forward must have different linkages

Answer 31

False: they only need to communicate different overall messages (A --| B --| C = A --> C)

Question 32

What is the relationship between the cAMP pathway and the PI3K pathway in polarization?

Answer 32

A coherent feed forward

Question 33

What does GSK3b stand for?

Answer 33

Glycogen synthase kinase 3 beta

Question 34

What does GSK3b do?

Answer 34

Regulates glycogen synthesis, and mediates polarization (and other functions)

Question 35

When GSK3b is phosphorylated, what state is it in?

Answer 35

Inactive

Question 36

When GSK3b is not phosphorylated, what state is it in?

Answer 36

Active

Question 37

What is the natural state of GSK3b in the cell?

Answer 37

Constitutively active

Question 38

What enzyme inactivates GSK3b?

Answer 38

Akt

Question 39

What enzyme sits in the middle of the crosstalk between the cAMP and PI3K pathway?

Answer 39

GSK3b

Question 40

Which amino acid regulates GSK3b function?

Answer 40

Ser9

Question 41

What state does GSK3b need to be in to promote axon development?

Answer 41

Inactive (phosphorylated) state

Question 42

What is a downstream effector of GSK3b?

Answer 42

CRMP-2

Question 43

What is the upstream regulator of CRMP-2?

Answer 43

GSK3b

Question 44

What does CRMP-2 do?

Answer 44

Regulates microtubule formation

Question 45

When CRMP-2 is phosphorylated, what state is it in?

Answer 45

Inactive

Question 46

When CRMP-2 is not phosphorylated, what state is it in?

Answer 46

Active

Question 47

What state does CRMP-2 need to be in to promote axon development

Answer 47

Active (non phosphorylated) state

Question 48

What does CRMP-2 stand for?

Answer 48

Collapsin-response mediator protein 2

Question 49

What is one of the most downstream effectors of axon formation and development?

Answer 49

Microtubule regulation

Question 50

What is the growth cone?

Answer 50

The tip of the neurites

Question 51

What is the tip of the neurite called?

Answer 51

The growth cone

Question 52

What happens at the growth cone?

Answer 52

Signaling for axonal development occurs, with constant shape changes

Question 53

True or false: the growth cone is a static structure

Answer 53

False: it is highly dynamic

Question 54

Where are the signaling pathways for axonal development centralized?

Answer 54

In the growth cones

Question 55

What is the structure of the growth cone?

Answer 55

Rich in actin and microtubule cytoskeleton

Question 56

What is the majority of the growth cone comprised of?

Answer 56

Actin cytoskeleton

Question 57

What does the actin cytoskeleton do in the growth cone?

Answer 57

Monitors and responds to the environment

Question 58

What does the microtubule do in the neurites?

Answer 58

Builds the stem of the neurites

Question 59

True or false: the actin and microtubule cytoskeletons in the growth cone do not interact

Answer 59

False: the microtubule can invade the actin network and regulate the shape of the growth cone

Question 60

What does the growth cone respond to?

Answer 60

Gradients of extracellular cues

Question 61

How does the growth cone respond to extracellular cues?

Answer 61

Through its receptors

Question 62

Where are the receptors to respond to extracellular cues (for axon formation) found?

Answer 62

In the growth cone

Question 63

What is the structure of the microtubules?

Answer 63

A hollow cylinder

Question 64

What are the monomers of the microtubules?

Answer 64

GTP-bound alpha and beta tubulin

Question 65

How many filaments comprise a microtubule?

Answer 65

13 filaments

Question 66

True or false: the microtubules are static structures

Answer 66

False: they are highly dynamic (can grow and shrink)

Question 67

True or false: microtubules are symmetrical

Answer 67

False: they have directionality (plus and minus end)

Question 68

What happens at the plus end of microtubules?

Answer 68

Adds tubulin subunits

Question 69

What happens at the minus end of microtubules?

Answer 69

It gets degraded

Question 70

What do plus end stabilizer proteins do?

Answer 70

Bind to the plus end of the microtubule and stabilize it (no synthesis)

Question 71

How does CRMP-2 work?

Answer 71

It binds to tubulin monomers and incorporates them into the microtubule

Question 72

Why does CRMP-2 need to be not phosphorylated to mediate microtubule formation?

Answer 72

It has a lower affinity for tubulin when it is phosphorylated

Question 73

When is CRMP-2 inactived?

Answer 73

When GSK3b is activated

Question 74

When is CRMP-2 activated?

Answer 74

When GSK3b is inactivated

Question 75

What happens to the cell when GSK3b is inhibited?

Answer 75

Multiple axons form

Question 76

What happens to the cell when GSK3b is constitutively activated?

Answer 76

No axons form

Question 77

What is needed in the axon (in terms of GSK3b and CRMP-2) to promote axonal development?

Answer 77

Unphosphorylated (activated) CRMP-2 and phosphorylated (inactivated) GSK3b