Lecture 3 - Axonal Growth - Tropism Flashcards
What is the first step in neuronal identity and the formation of connections?
Polarization (and is a primary property of all cells).
A neuron starts round with
no obvious processes (neurites).
Over time the neuron (neurite) begins to
extend multiple processes and becomes multipolar.
What defines the polarity of the neuron?
One of the multiple processes become the axon, which then defines the polarity of the neuron.
What is at the tip of the axons?
a specialized structure (or structures) called growth cones.
Where is the growth cone located?
specialized motile structure at the tip of extending axon
What does the growth cone do?
explores extracellular environment, determines direction of growth, and guides extension of axon; key decision-making structure in axon pathfinding morphological characteristics
lamellapodium –
fan-shaped sheet at tip of axon; contains actin filaments and microtubules
filopodia –
fine processes extending out from lamellapodium; contain actin filaments; form and disappear rapidly
How does the leading edge of filopodium respond to environmental cues?
Gobular actin (G-actin) can be incorporated into filamentous actin (F-actin)
A key to growth cone turning is
the binding of F-actin binding proteins to F-actin, which regulates retrograde flow.
In growth cone tuning what regulates retrograde flow?
The binding of F-actin binding proteins to F-actin
What happens when encountering an attractive cue?
assembly is increased and retrograde flow slowed causing turning towards the attractive cue (repulsion is the opposite)
What is the role of microtubules in growth cone tuning?
1) It makes the core of the cytoskeleton in the axon extremely stable and strong 2) Modulation of interactions with microtubules modulate stability and turning of the axons.
What are primarily responsible for axon elongation?
Microtubules
In growth cone signaling what dictates direction?
F-actin
How can discrete regions of the growth cones be detected?
by different types of actin and tubulin
F-actin is in
lamellipodium and filopodia
Tyrosinated microtubules are enriched in
lamellipodia
Acetylated microtubules are only in
the axons.
In axonal growth, what happens at decision points?
The growth cone shape changes
What are the axon guidance signals?
There are 4 types - non-diffusible (short-range) signals: 1) contact attraction 2) contact repulsion diffusible (long-range) signals: 3) chemoattraction 4) chemorepulsion
What is the function of the axon guidance signals?
all 4 types may act in concert to guide axon to appropriate target; ensures accurate guidance
What does the binding of axon guidance molecules to receptors do?
on growth cones binding activates signaling cascades that result in reorganization of the growth cone cytoskeleton which controls the direction and rate at which the growth cone moves.
What do attractive growth cone interactions do?
they promote actin polymerization in the direction of the attractive molecules
What do repellent growth cone interactions do?
promote actin depolymerization and growth cone collapse.
In the peripheral nervous system what are the non diffusible guidance molecules
laminins, collagens and fibronectin are attracive substrates for growth cones
In the peripheral nervous system, what happens to the non diffusible substrates?
these substrates bind to growth cone receptors called integrins, which triggers a series of signaling cascades leading to axon growth and elongation
Describe the ECM molecules in the CNS.
They are expressed at low levels
Matrix of the CNS is mostly composed of
hyaluronan, proteoglycans and glycoproteins but it lacks many of the “typical” matrix molecules (laminins, collagens, fibronectin)
For non-diffusible guidance molecules, how would you describe the CNS extracellular matrix molecules
they are largely repulsive
Describe the nondiffusible guidance molecules, CAMs.
They are attractive
Where are the CAMs of the CNS located?
Located on surface of growing axons, growth cones, and surrounding cells or targets
What do CAMs act as?
ligands and receptors typically via homophilic binding; attractive interaction
What is the relationship between CAM and Calcium?
Calcium independent
Ligand/receptor CAM interaction does what?
induces interaction with cytoplasmic kinases in growth cone
L1 CAM
has been associated with fasciculation (bundling) of groups of axons as they grow
Non-diffusible guidance molecules; cadherins
they are attractive
Where are cadherins located?
On the surface of growing axons, growth cones and surrounding cells or targets
What do cadherins act as?
Act as ligands and receptors typically via homophilic binding; attractive interaction
What is the relationship between calcium and cadherin?
Calcium dependent
What does the Ligand/receptor interaction for cadherin trigger?
intracellular signaling pathways that lead to actin binding and organization
Describe the non diffusible guidance molecules, semaphorins
mostly repellent
Are Semaphorins diffusible or non diffusible?
non-diffusible
Where are semaphorins located?
Can be secreted or anchored to the cell surface; secreted forms are probably attached to the cell surface or the extracellular matrix, so they are not really diffusible
Are semphorins attractive or repellent?
Mostly repellent, but have also been shown to be attractive in some situations
What happens to semaphorins receptors?
Receptors on growth cones are members of the plexin family; cell surface forms bind directly to plexins, while secreted forms bind neuropilins which then complex with plexins
What do cell surface semaphorins bind to?
The bind directly to plexins
What do secreted semaphorins bind to?
Bind neuropilins which then complex with plexins
What does semaphorin ligand/receptor interaction result in?
growth cone collapse and inhibition of axon extension via receptor interaction with intracellular signaling molecules
What do semaphorins promote?
Growth cone collapse
Are ephrins diffusible or non-diffusible?
Non-diffusible
Are ephrins attractive or repellent?
repellent
What are ephrins?
Cell surface signaling molecules similar to cell adhesion molecules
What are the classes of ephrin?
1) ephrin-A = GPI-linked to cell surface 2) ephrin-B = single pass transmembrane proteins
What does each class of ephrine have?
Each has its own set of receptors on growth cones, eph A receptors and eph B receptors, that are receptor tyrosine kinases
What type of receptors are ephrin receptors?
Receptor tyrosine kinases
What does ephrin interaction with its receptor on the growth cone results in?
a repellent interaction that collapses the growth cone
In the developing brain axons from the retina make
precise connections with the optic tectum (in frog and chick).
What are the connections from the retina to the optic tectum?
1) Temporal retina to anterior tectum 2) Nasal retina to posterior tectum