Lecture 4: Construction of Neural Circuits Flashcards
Neuronal polarization
The formation of axons and dendrites
As neuroblasts/ immature neurons complete their migration, they extend axons and dendrites guided by scaffolding cells and molecular gradients (POLARIZATION)
IN CULTURE neuronal polarization (based on in vitro observation):
Stage 1: lamellipodia surrounding periphery
Stage 2: appearance of ‘symmetric’ neurites
Stage 3: break of symmetry by differential growth rate
Stage 4: remaining neurites become dendrites
Stage 5: final mature neuron
neurites become
dendrites
Formation of Axons and Dendrites steps
- Symmetry breaking cue (local signals, eg: secreted molecules)
- Local signal amplification (expression of PAR proteins, polarity regulator, and signalling of future axon)
- Cytoskeletal rearrangement (cytoskeletal redistribution and establishment of polarity)
Neuronal polarity
axon and dendrites are structurally (and functionally) different
Axons:
microtubule + ends out (away from soma) -end towards soma
Axons -
Kinesin (anterograde transport) + Dynein (retrograde transport)
motor proteins for anterograde and retrograde transport via MT tracks (more particles/vesicles from/to soma)
Dendrites
MTs (microtubules) of mixed polarity (+/- ends mixed, some out and some inwards)
Golgi outposts (proximal) and satellites (distal) contribute to dendritic outgrowth
F-Actin in Dendrites
serve as tracks for local transport of mRNA and proteins to dendritic spines by Myosin V (myosin binds to actin, binds to dendritic spines)
Neuronal Growth Cones:
specialized structure at the tip of a growing neurite (Highly motile), exits in dendrites, not fully differentiated
- Critical for sensing environment and finding targets
what are the components of neuronal growth cones
lamellipodium = Expansion of the cone (tubulin)
filopodia = Finger-like projections at the distal tip (actin)
Chemotaxis = chemotropism
the attraction or repulsion of growth cones (senses environment cues to determine final destination) by certain molecule
Chemoattractant : Diffusible signals (long range):
Form a concentration gradient
e.g., (+) netrin; slit
e.g., (-) semaphorin
tropic
Chemorepellent: Non-diffusible signals (short range):
e.g. (+) ECM proteins (laminin, fibronectin) with cell membrane-bound integrins
e.g. (+) Cell adhesion molecules (CAMs, cadherins)
e.g. (-) Ephrins (can be chemoreplants or opp. effect)
tropic
Extension and change in direction require (The molecular basis of growth cone motility)
depolymerization and polymerization of tubulin (lamillopodium and shaft) and actin (leading edge of lamillopodium and filapodia) axon needs to determine where to go, helps neuron migrate and reach final synapse
- ATP-dependent
what is growth cone motility regulated by
- Attractive and repulsive cues
- actin and tubulin binding proteins
- changes in [Ca2+]I via voltage-gated Ca2+ channels, transient receptor potential (TRP) channels and/or internal stores
Ca2+ is important for in Growth cone behavior and axonal growth:
- Axonal and cone growth
- Turning when approaching its target:
- Ca2+ release from the ER guides polymerization and attraction
- Ca2+ influx from the extracellular space (through Ca2+ channels) induces depolymerization (breaking down microtubules and actin filaments) and repulsion
Growth cone wants to grow towards
chemoattraction (needs depolarization)
Polymerization:
actin filament grows
Depolymerization:
actin filament doesn’t grow
Polarized dendritic growth ALSO relies on extrinsic signal
Semaphorin 3A (can be short-range, not secreted, or secreted and released, long range) acts as both a chemoattractant (dendrites) and a chemorepulsive (axon) signal based on the activity of a soluble guanylyl cyclase (sGC - receptor) that is available in dendrites but not in axons
main events of the construction of neural circuits
Main events:
* Neuronal migration to final destination
* Neuronal polarization (part of differentiation)
* Apoptosis (Initial refinement – tropic
support dependent)
* Synaptogenesis
* Myelination
* Synaptic pruning and further
refinement/modification to generate mature
circuits
PAR protein
(polarity regulator) - singling of future axon
tropic vs trophic molecules
“tropic” hormones target other endocrine glands (cams, ephrins, ecm..) , while “trophic” molecules promote growth, survival, and differentiation of target cells, often in the nervous system (NGF)
