Growth Cones Flashcards
How does a neuron grow
As it extends, it leaves behind a cytoplasmic trail (axon)
Growth cone defined by cajal
Club/battering ram
Endowed by chemical sensitivity which makes it able to arrive to its destination
What are the functions of the growth cone
-sensor and motor for axon growth
-perceives and responds to signals in the environment
-Provides motile force for axon and neurite extension
-aids target recognition
How is axon growth directed (what do they prefer?)
Growth cones prefer more adhesive substances
What are the substances growth cones show preference for
Laminin
Polylysine
How is axon growth directed
By diffusible molecules (netrin) which is an attractive cue for axons
Axons grow towards cues
Long range cues examples
Chemorepulsion (slit netrins)
Chemoattraction (netrin)
Example of short range cues
Contact repulsion (semaphorins,ephrins)
Contact attraction (IgCAMs)
Two dynamic structures in growth cones
Filopodia (actin filaments)
Lamellipodia (actin mesh)
What does the central core of the growth cone contain
Microtubules
Mitochondria
What are the three regions of the growth cones
Central region (microtubule rich)
Transitional region
Peripheral region (F-actin)
What are lamellipodia and filopodia made up of
Dynamic bundles of actin and tubulin which continuously polymerise and depolymerise
What is axon treadmilling
Actin added to top, removed from the bottom
3 approaches to understand growth cone migration
Genetic
In vivo/biochemical
Visualisation
Genetic approach to understand growth cone migration
Identify mutations that disrupt axon growth using c elegans and drosophila
In vivo/biochemical approaches
Primary cultures of neurons (hippocampal/cortical/retinal)
Add cytoskeletal modifiers
Visualisation approaches
GFP labelled molecules to visualized growth cone migration
Role of growth cone
Directs axonal outgrowth
Where is the growth cone steered towards
Filopodia dilation occurs where the is a greater concentration of diffusable cue, there is more polymerisation
Actin polymerisation and depolymerisation
Actin added to + (barbed end)
Actin removed from - (pointed end)
Retrograde flow of actin monomers
Microtubule polymerisation and depolymerise
Tubulin added at + end
Tubulin removed from - end
How does net extension occur
Polymerisation is greater than disassembly
Role of actin depolymerising drugs
Slows axonal extension
Prevent growth cone turning
What does growth cone turning require
Microtubule polymerisation
Engorging filopodium forms the new axon segment
What do microtubules polymerise into
Filopodia where actin filaments have been stabilised
What are microtubule associated proteins
TIP proteins for monomer addition (APC/CLASP/EB3)
Destabilizing proteins (Kif 2A, C/SCG10)
Motors (kinesins and dynein)
Severing proteins (spastin/ katanin)
Stabilizing proteins (MAP1b/Tau/DCX)
What causes microtubule invasion of filopodia
Proteins that bind to actin filaments and microtubules
What does growth cone progression require
Myosin and interaction with matrix via cell adhesion proteins (CAM/SAM) - which allows adhesion and movement
How do growth cones detect cues
Receptors on their surface detect guidance factors e.g. netrin/slit
Example growth cone receptors
Robo (changes as growth cone extends)
Stages in protrusion
Tip complex activation - bundled actin polymerisation resulting in filopodial extension
Actin capping - creation of dendritic network for protrusion
Actin severing - new barbed ends for growth
Stages in retraction
Actin bundle and network loss - inactivation of barbed end protractor proteins, inactivation of bundling proteins , severing without polymerisation, retrograde actin flow maintained
Microtubule shrinkage/destabilization- increased catastrophe, decreased rescue
Cytosketal regulators which direct growth cone navigation
Guidance cues and receptors
Primary responder molecules
Integration (G proteins)
Coordination
Cytoskeletal effectors
Effect
Role of GAPs
Rho GTP (active) —-> rho GDP (inactive)
Role of GEFs
Rho GDP (inactive) —-> Rho GTP (active)
Robo (roundabout) mutant
Axons in wrong direction
