Axon Growth & Target Innervation Flashcards
Fundamental cellular unit of the NS?
Neuron
What is the growth cone?
The motile structure at the distal tip of an elongating neuronal axon
Axons are guided by simultaneous and coordinate actions of 4 types of guidance mechanisms:
- Contact attraction
- Chemoattraction
- Contact repulsion
- Chemorepulsion
How do axons know when to stop growing?
Ephrin binding to Eph-A receptors causes growth cone collapse
What controls the direction of axon growth in the developing brain?
Axonal guidance cues
pre and perinatal exposures that alter brain development and therefore alter the levels of guidance cues which will ultimately change the patterns of brain wiring
4 major families of guidance cues
Semaphorins, Netrins, Slits and Ephrins
Why are there multiple families of guidance cues?
We have these multiple guidance cues from multiple families because it lowers the risk of guidance errors and improves the accuracy of wiring of the nervous system rather than relying on a single molecule
What does the floor plate secrete
Shh and Netrin
How is embryonic axonal navigation accomplished?
By the axonal growth cone
What did Harrison and Speidel identify?
The growth cone as a key decision-making component during axon growth
Growth Cone structure
Thin, fan-shaped sheet (lamellipodia) with many long, thin spikes (filopodia) radiating forward to sense the environment
What happens if the GC collapses
Neurons cannot extend the axon
What are crucial for growth cone steering?
Cytoskeletal dynamics - actin filaments & microtubules
What two key events are required to sprout a neurite?
- Filopodium adhering to adjacent extracellular structures
- Microtubules advancing into an adherent filopodium
What does the growth cone detect as it travels towards its synaptic target?
Extrinsic cues
What do surface receptors on the lamellipodia & filopodia detect? And what is the result of this?
Detect intrinsic cues - triggers changes in cytoskeletal & membrane dynamics, which turn the growth cone (i.e. navigation)
What is a major target of guidance cue signals?
Axon and microtubule filament network
Guidance cues are linked to __ , which activate intracellular signalling pathways
Rho-GTPases
How do Rho-GTPases affect cytoskeletal dynamics
They regulate actin-binding and microtubule-binding proteins, which control the organisation & distribution of actin filaments & microtubules
Examples of repulsive cues
Semaphorin3A and EphrinA
How do repulsive cues affect actin polymerisation?
Repulsive cues switch on the GTPase RhoA, which reduces GC protrusion and promotes actin depolymerisation
Examples of attractive cues
Neurotrophin and Netrin
How do attractive cues affect actin polymerisation?
Attractive cues switch on the GTPases Rac1 and Cdc42, which increases GC protrusion and promotes actin polymerisation
guidepost cells?
Axons navigate successive segments on their trajectories to distant targets. Each segment has a group of cells that act as an intermediate target for growth cones of axons. These cells are termed ‘guidepost’ cells.
What happens when Netrin-1 is knocked out in mice
There’s significant misrouting of commissural axons, with many failing to reach the floor plate due to lack of guidance by Netrin-1.
Do diffusible members of guidance cue families function in long- or short-range axon guidance?
Long range
Why might different axons respond to the same cue differently
Expression of different surface receptors or intracellular signalling molecules
The 2 major groups of guidance cues
Canonical and non-canonical
Netrins bind to receptors of which families?
DCC and UNC5
How can attractive effects of Netrin-1 on the GCs of axons, which are mediated by DCC receptors, be converted to repulsive effects?
By introducing an UNC5 family member into the neuron
What does Netrin bifunctionality depend on?
Receptor composition of axon
Different forms of Semaphorins
Secreted, transmembrane, or GPI-linked
What do Semaphorins bind?
Plexins and neuropilins (NPN)
Slits bind to receptors of which family
Robo
How do filopodia act as scouts for less advanced portions of GC?
Either by seizing hold of permissive substrates or avoiding inhibitory substrates to reorient GC extension
How does guidance cue signalling regulate actin dynamics?
By directly or indirectly altering the activity of Rho-GTPases, which regulate actin polymerisation
What Rho-GTPase does Netrin receptor DCC activate
Rac
Semaphorin receptors activate __ via an adaptor protein, that stimulates exchange of GDP for GTP on the GTPase.
Rho
What is topographic mapping?
Many axonal projections within the brain establish an orderly arrangement of connections within their target field, termed a topographic map
How is a smooth and continuous topographic map formed?
By neighbouring cells projecting to neighbouring parts of the target
What cell type has been widely studied in terms of topographic mapping
Retinal ganglion cells (retina projection to superior colliculus)
What was the Chemoaffinity Hypothesis
Molecular tags on projecting axons and their target cells determine the specificity of axonal connection within a neural map (i.e. molecular mapping rather than functional moulding of random connections)
Axons from the temporal side of the retina grow towards…
the rostral side of the tectum
Axons from the nasal side of the retina grow towards…
the caudal side of the tectum
What did Friedrich Bonhoeffer develop?
An in vitro assay called the membrane stripe assay - first demonstration of a role for repellent activities in axon guidance
Two major advances in mid 1990’s regarding axon guidance
- Cloning of two related genes, EphrinA2 and EphrinA5
- Development of new methods of axon tract tracing (fluorescent dyes)
What receptors do Ephrins bind to?
RTK Eph receptors
EphrinA binding to EphA induces…
growth cone collapse (crucial in R-C mapping)
Wnt3a cooperates with __ binding to regulate D-V mapping
EphB-EphrinB1 binding
EphrinB binding EphB __ growth cones
repels (chemorepulsion)
EphrinA2/A3 double knockout mice present with
ASD
