Lecture 14: Neuronal Growth and Guidance Flashcards
Where does the CNS form from?
- Ectoderm
- Through formation of neural tube
Where are neurons ‘born’?
- Ventricular zone of neural tube
Where do neurons migrate, along what?
- Migrate outward
- Along radial glial cells
- Where they differentiate and become functional
What is cellular polarization? What does it depend on?
- Process by which cell polarity is determined
- Depends on protein interactions within the cell
What determines cell polarity?
- Apical (top) vs. Basal (bottom) surface
- Epithelial cells
- Apical = faces lumen (takes in and releases molecules)
- Basal = intercellular protein exchange
What does the apical domain have?
- Distinctive actin cytoskeleton and villi
- Increase surface area for taking in and releasing molecules
Where is the Golgi apparatus oriented toward?
- Apical membrane
What does the basal domain make contact with?
- Extracellular matrix
- Contains ion channels and signalling molecules for intercellular protein exchange
Where are the ends of microtubules oriented toward?
- Basal membrane
Where is the site of endosomal traffic?
- Basal membrane
What happens after neuroblast enters postmitotic state?
- Neurites begin to grow
- Undifferentiated small extensions from neuroblasts that have neither axonal nor dendritic identities
What leads to the identification of a single process as the axon?
- Microtubule and actin cytoskeleton components (including PAR) are redistributed across multiple neurites
- PAR is a ‘polarity regulator’
What needs to occur after axon specification?
- Growth needs to occur to form synapses
What are growth cones?
- Specialized ends of growing neuroblast processes
- Found in both axon and dendrites
- Leading edge of growth (‘hand-like’)
- Consisting of:
- Sheet-like structures (lamellipodia)
- Finger-like structures (filopidia)
Are filopodia permanent?
- No
- They rapidly form and disappear
What do filopodia do?
- Explore extracellular environment, determine growth direction, guide axon extension in that direction
How do the cytoskeletal molecules of filopodia compare to those of an axon?
- Axonal growth depends on ATP-dependent modification of the actin and microtubule cytoskeletons
What is the actin of a growth cone responsible for?
- Lamellipodial and filopodial morphology for directed growth
What are the microtubules of a growth cone responsible for?
- Elongating the axon
Where is Filamentous actin (F-actin) found?
- In lamellipodium and filopodia
Where are tyrosinated microtubules found?
- Tubular components of lamellar region
Where are acetylated microtubules found?
- Tubular components of the axon
What is a filopodium? What is it stabilized by? What does it do?
- Leading edge of growth cone
- Stabilized by actin (primarily F, also globular)
- Forms polymers in response to attractive cues, and depolymerizes in response to repulsive cues
What is the lamellipodium? What does it do/how is it stabilized?
- Trailing edge of growth cone
- Microtubule subunits at junction of axon/lamellipodium
polymerize to stabilize axon cytoskeleton - Used for structural integrity and transporting proteins from soma to axon terminal
What are actin and tubulin binding proteins responsible for?
- Regulate assembly/disassembly of subunits into filaments or tubules
- Ca2+ process via voltage-regulated Ca2+ channels and transient receptor potential (TRP) channels
Which type of actin expands the lamellipodium?
- G-actin
Which type of actin expands the filopodia?
- F-actin
Is polymerization within growth cones dependent on Ca2+ presence?
- Yes
How is the growth cone calcium-mediated?
- Intracellular Ca2+ via voltage-regulated Ca2+ channels
- Transient receptor potential (TRP) channels
- Ca2+ fluctuations are highly localized and influence very specific regions (allows for targeted growth direction)
Where do axonal growth cones change shape?
- At ‘decision points’
What shape are axons travelling ‘familiar’ pathways?
- Remain simple shape
How is the shape affected for ‘pioneer’ axons?
- Change dramatically
- Sends out extensive filopodia in ‘search’ of appropriate guidance cues
What does the direction of the growth cone depend on?
- Molecular signals in embryonic environment
What is the role of adhesion molecules in cell guidance?
- Found in extracellular matrix
- Ex. Laminins, collagens, fibronectin
- Non-diffusible signals for axon guidance
- Rather, form extracellular polymers
- Signal growth attraction/repulsion
What do cells bind to?
- Bind to cell surface receptors
- Integrins
What do CAMs do?
- Associated with bundling groups of axons (fascicles)
- Keep growing axon on path of pioneer
What do cadherins do in cellular guidance?
- Determine final target (where cell stops) selection in transition from growing axon to synapse
What are ephrin ligands responsible for?
- Cell-cell recognition
- Indicate to approaching cell that another cell is there
Describe chemoattraction?
- Target-derived tropic signals that attract growth cones to a destination
- Target that wants growth cone to approach released chemoattractants
Describe chemorepulsion?
- Signals that repel/discourage axon growth toward inappropriate areas
- ‘stay away’
What is an example of a chemoattractant? What does it bind to?
- Netrin
- Binds to DCC receptors
- Filopodia with polymerize/grow in that direction
What are 2 examples of chemorepellants? What do they bind to?
- Slit
- Binds to robo receptors
- Filopodia depolymerize and head in different directions
- Semaphorins
- Bound to cell surface/extracellular matrix
- Prevent extension of nearby axons (helps claim area)
What does actin regulate?
- Changes in shape of lamellipodia/filopodia
What do microtubules regulate?
- Elongation of axon
What is G-actin?
- Freely soluble monomer
What is F-actin?
- Polymers that form filaments
Where do commissural neurons send axons to?
Commissural = massive fibre tracts crossing the midline
- Send axons to ventral region of spinal cord
- Includes floorplate
What does the floorplate release?
- Netrin and slit
How does the axon interact with the floorplate in order to cross the midline?
- Axon initially attracted by netrin (insensitive to slit)
- After crossing midline, slit binding to robo receptor desensitizes axon to netrin
- Prevents recrossing of midline (repels axon)
What does the addition of semaphorin do to growth cones? What is this dependent on?
- Collapses axonal growth cones
- Calcium dependent effect
What does dendritic polarization underlie?
- Information processing
- Particularly in retinal ganglion cells, Purkinje cells, and cortical pyramidal neurons (unique and dynamic growth)
How does Semaphorin 3A interact with axons/dendrites?
- Repels axon of developing neuron
- Attracts dendrites
- High concentrations in developing cortex helps ensure proper development of laminar organization
How does slit1 interact with projection axons?
- Repels projection axon growth to keep it toward ventricular rather than apical surface of cortex
What does Local Notch signalling do?
- Locally reinforces semaphorin effects
What does BDNF do?
- Promotes growth
Why do dendrites need to arborize appropriately?
- Give enough space to provide adequate coverage of space
- Dendritic tiling (self-avoidance and other-avoidance)
What does dendritic tiling require?
- Dual repulsion
- Respond to self-released and other-released signals
What is dendritic arborization dependent on?
- DSCAM gene
- On human chromosome 21
- Down syndrome cell adhesion molecule
What do DSCAM mutations lead to?
- Cell tiling failures
- Tangles within same cell
- Clusters of dendrites overlapping/interfering
