L1 - Neuronal Polarity Flashcards by Jack Corston

What does neuronal polarity mean?

That the two ends of a neurone are different

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Fucntion of the axons

Responsible for AP generation

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Function of dendrites

Collect and integrate the incoming stimuli

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3 ways in which axons and dendrites are distinct

Structurally
Molecularly
Plama Membrane

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How are axons strucutually different from dendrites

AXONS - highly polarised MTs

DENDRITES - MT less ordered and have mixed orientations

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What molecule would be found in axons not dendrites

Tau - microtubule assocaited protein

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What molecule would be found in dendrites and not axons

MAP2

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How is the PM membrane of axons different dendrites

AXONS - CAM L1

DENDRITES - GluR1

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What is GluR1

Subunit of the glutamate receptor

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What experiemntal method could be used to determine any barriers that exist in a neurones membrane

Using optical tweezer

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What were the results of an optical tweezer experiments to test for barriers in a neurones membrane

Proteins coated in axon protein cant move into the dendrite

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The barrier in a neurone is called the

Axon initial segement

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What does the AIS maintain

Somatodendrtic and axonal domains

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Who set up the hippocampal neutrite selection paradigm

Dotti et all 1988

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Describe the results of Dottis neurite selection paradigm

Neuron starts as a spherical cell and then progresses extending spouts before finally selecting the aoxn

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What can axon selection be visualised with

How does this work?

Kif1-GFP

GFP with Kif1 is a plus end directed kinesin so travels to the + end of the microtubule so can see where the axons are forming

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The process of axon selection is ______

Stochastic

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What does stochastic mean

A process that appears to be random but full picture might not be understood

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How does axon selection happen

All of the neurites are tried and tested before one is selected

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What do growth cones and neurites contain?

Dynamic MTs that are tyrosinated

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What do newly polarised axons contain/

Stabilised and acetylated microtubules

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What can be used to stabilise artifically a microtubule

Taxol

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What happens if you cut a newly specified axon?

Selection of another neurite to become the axon

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What are the roles for positive and negative feedback in axon selection (TWO)

A) diffusible inhibitor which prevents axon formation in neurites
B) a limitting component

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What happens when Hras expression is forced in neurones

Forms a neurone with mutliple axons

Where does Hras accumulate - what does this cause

Accumulates in the growth cone as symmetry is broken

What is the effect of using a PI3K inhibitor

HRas prevented from accumulating in the growth cones ALSO prevents the induction of multiple axons by HRas overexpression

The results obtained through the PI3K inhibitor use shows that ...

HRas works through PI3 kinase

What can be used to activated PI3 kinase

iRAP

Activation of PI3 kinase causes

The activation of HRas

HRas and PI3 kinase act in a ......

Mutually dependent pathway

HRas is depeleted from _____________ This is consistent with the _________________ model

Non-axonal regions Limiting component model

What type of molecule is Ras

A GTPase

What is the effect of activated Ras

Activation of PI3 kinase | Phosphorylation of PIP2 --> PIP3

What does PIP3 activate what does it inhibit

ACTIVATE Akt ACTIVATE Rac INHIBITOR GSK-3B

What is the effect of GSK3B when it HASNT BEEN PHOSPHORYLATED by PIP3

Inhibition of microtubule stabilisation

With Activation of Akt and Rac and the inhibition of GSK-3B what is the overall effect

Microtubules stabilsing and actin dynamics triggered Leads to actin elongation

What do the par genes establish

Asymmetric cell division

What is the first role of the Par genes

Establish polarity following sperm entry

What makes up the Par3 complex

CDC42 PAR6 PAR3 PKC-3

Where do Par3 complex proteins localise

In the nascent growth cone

Par6 is member of

Par3 complex

What antagonises PI3 kinase .... how>

PTEN Phosphatase that acts on PIP3

Why is PTEN important in cells

To prevent CA of PIP3

What is the result of PIP3 inhibition by PTEN

Prevention of Par3 accumulation blocks axon formation

SAD kinases related to

Par1

What is the result of a loss of SAD kinase

Failure of acetylated (stable) tubulin to predominate over tyrosinated tubulin = no axons are formed

What is the result of a loss of LKB1 kinase

Failure to make axons

Describe the model of LKB1, Par3 complex and SADK in axon specification

Normally LKB1 inhibits Par3 complex prevening it inhibiting GSK3B LKB1 phosphorylation inhibits this inhibition (causing activation of GSK3B) and causes activation of the SAD kinases SAD kinase activation is required for specification of the axons

What phosphorylates LKB1

Phosphorylation by PK-A

What is the action of the phosphorylated LKB1

Activation of SAD kinases

What is the action once the SADkinases have been activated

MAP stability and axon initiation

What is the function of the Par3 complex in axon formation in vivo

Par3 and PI3K inhibit the inhibition of axon formation by GSk3B also affeected MAPS

What is the result of LKB1 loss in the mouse cortex

Loss of axon initiation

What are tubulinopathies

Diseases where mutations are of tubulin

What is milder mental retardation associated with

TGFB receptor mutations

Where are TGFBs expressed? And what is their role

Expressed in the VZ of the developing cortex | Can initiated axons in vitro

What are the flavours that semaphorins come in?

Membrane bound | Secreted

Describe the Sema3A gradient ... what does this gradient do?

Gradient from basal to apical which attracts dendrites basally it also promotes dendrite formation at the expense of axons

What is the mechanism by which Sema3A works

Raises levels of IIC cGMP and supresses cAMP | Inhibtion of PK-A so it is blocked from the phosphorylation of LKB1 and GSK3B

Manipulation of cAMP and cGMP has ______ effects on axon formation

OPPOSITE

TGFB activates the

Par3 complex

Members of the Par3 complex include

Par3, Par6, aPKC

Appically _____ phosphorylates _____ (member of the _______) to promote _____-

TGF-B Par6 Member of Par3 Axon specification

Basally ____ increases _______ and decreases _____ thus ______________by ________________ this prvents activation of __________ which is responsible for _______________

Basally Sema3a increases cGMP and decreases cAMP thus preventing phosphorylation of LKB1 by PK-A Prevnets the activation of SAD kinase which is responsible for axon specification

Evidence for polarity inheritance

In the retina are early cortex, neurones born from radial glia

Evidence against polarity inheritance

Later cortex, dividing intermediate progenitors that expand neurone numbers, these lose their polarity during division and it must be re-established