Axonal Growth, Synaptogenesis, Tropism Flashcards
1
Q
neuronal polarization
A
- first step in neuronal identity and the formation of connections
- neuron starts round with no obvious processes
- over time begins to extend multiple processes and becomes multi polar
- one of the processes become the axon, which defines the polarity
- at the tip of the axon is growth cone
2
Q
growth cone
A
- specialized motile structure at tip of extending axon
- explores extracellular environment, determines direction of growth, and guides extension of axon
- key decision making structure in axon pathfinding
- lamellapodium-fan shaped sheet at tip of axon, contains actin filaments and MT
- filopodia-fine processes extending out from lamellapodium, contain actin filaments, form and disappear rapidly
3
Q
cytoskeletal elements in growth cones
A
- G actin can be incorporated into F actin at the leading edge of filopodium in response to environmental clues
- key to turning is binding of F actin binding proteins to F actin, which regulates retrograde flow
- when encountering an attractive cue assembly is increased and retrograde flow slowed causing turning towards the attractive cue
- MT make the core of the cytoskeleton in the axon-extremely stable and strong
- modulation of interactions with MT modulate stability and turning of the axons
- MT responsible for axon elongation, F actin dictates direction
4
Q
F actin
A
-in lamellipodium and filopodia
5
Q
tyrosinated MT
A
-in lamellipodia
6
Q
acetylated MT
A
only in axons
7
Q
axon guidance molecules
A
- non-diffusible-short range-contact attraction and repulsion
- diffusible-long range-chemoattraction/repulsion
- all four types may act in concert to guide axon to appropriate target
- binding of axon guidance molecules to receptors on growth cones turns on cascades that result in reorganization of the growth cone cytoskeleton which controls direction and rate at which growth cone moves
8
Q
ECM molecules
A
- non-diffusible guidance molecules
- attractive
- collagen, fibronectin, laminin
- bind to integrins on growth cone
- mostly PNS
9
Q
CNS ECM molecules
A
- non diffusible?
- largely repulsive
- hyaluron, proteoglycans, glycoproteins
- poorly understood
10
Q
cell adhesion molecules
A
- non-diffusible
- attractive
- on axons, growth cones, surrounding cells/targets
- act as ligands and receptors via homophilic binding
- calcium independent
- ligand/receptor interaction induces interaction with cytoplasmic kinases in growth cone
- L1 CAM associated with fasciculation of groups of axons as they grow
11
Q
cadherins
A
- non-diffusible
- attractive
- located on axons, growth cones, surrounding cells/targets
- act as ligands and receptors via homophilic binding
- calcium dependent
- triggers intracellular pathway that lead to actin binding and organization
12
Q
semaphorins
A
- non-diffusible
- mostly repellent
- can be secreted or anchored to the cell surface
- secreted forms are probably attached to the cell surface or ECM
- receptors on growth cones are plexin family, cell surface forms bind directly to plexins, secreted forms bind to neuropilins then plexins
- results in growth cone collapse and inhibition of axon extension via receptor interaction with signaling molecules
13
Q
ephrins
A
- non-diffusible
- repellent
- cell surface signaling molecules similar to CAM
- A-GPI linked to cell surface
- B-single pass transmembrane proteins
- each class has receptors on growth cones, receptor tyrosine kinases
- collapses growth cone
14
Q
optic tectum
A
- axons from retina make precise connections with tectum
- temporal to anterior
- nasal to posterior
- ephrins are expressed in an AP gradient with higher concentration on posterior side (more ephrins in the back-pushes temporal axons to front)
- axons from temporal retina are repulsed by ephrin in posterior tectum
- axons from nasal retina bind to ephrin because they lack the receptor
15
Q
netrins
A
- diffusible
- attractive or repellent-depends on receptors
- secreted by target cells in midline of embryo
- attractive receptors are DCC fam
- repellent are UNC5 fam-activate Rho/GAPs and disassemble actin
- K/O of netrins stops crossing over of commisural axons
16
Q
slits
A
- diffusible
- repellent
- bind to Robo and activate Rho/GAPs and disassemble actin
17
Q
netrin and slit at midline
A
-help form commisural axons Problems: 1. cell first avoids target cell on same side 2. crosses at specific site 3. once crossed as not to re cross 4. has to find target cell on other side
18
Q
crossing over
A
- comissural axons express DCC and are originally attracted to the midline (produces high levels of netrin near midline)
- as they cross midline they upregulate Robo which keeps them from crossing back because of high level of slit at midline
- cross talk b/n Robo and DCC, Robo inhibits DCC and lose response to netrin
19
Q
axon guidance cues
A
- work in concert to guide growth cones
- multiple molecules line the pathways
- growth cone has to incorporate all the information
20
Q
selective synapse formation
A
- after reaching final target region, axons must decide which cells to innervate
- synaptogenesis is best understood in peripheral nervous system- NMJ
21
Q
synaptogenesis at NMJ
A
- motor axon approaches and makes contact with a myotuble
- both nerve terminal and myotubule differentiate after contact has been made-nerve becomes motor terminal and muscle with post-synaptic
- differentiation of muscle induced by agrin, which activates MuSK, causing clustering and increased local expression of Ach receptor through rapsyn
- both the motor nerve and the muscle make ECM components to form BL, stabilizes the synaptic structure
22
Q
synaptogenesis in superior cervical ganglion
A
- T1 and T4 axons use same long range guidance cures, but each innervates a different set of neurons- T1 to eye, T4 to ear
- synapse formation muscle be selective- the correct pre/post synaptic neurons have higher affinity for each other
23
Q
synaptogenesis in CNS
A
- nascent presynaptic process, from growth cone, recognizes an appropriate site on the target cell via cadherin/procadherin family
- synaptic vesicles and active zone components begin to accumulate
- additional adhesion molecules, including neurexin in the presynaptic membrane and neuroligin in postsynaptic membrane are recruited to synapse
- adhesive signaling initiates differentiation of the presynaptic active zone and postsynaptic density
- neurexin helps localize cytoskeletal elements, synaptic vesicles, active zone proteins and voltage gated Ca channels to presynaptic
- neuroligin recruits nt receptos and other postsynaptic proteins to postsynaptic membrane
- considerable diversity
24
Q
neurexin
A
localize cytoskeletal elements, synaptic vesicles, active zone proteins and voltage gated Ca channels to presynaptic
25
Q
neuroligin
A
nt receptos and other postsynaptic proteins to postsynaptic membrane
26
Q
trophic interactions between neurons and targets
A
- neurons become dependent on targets for survival and differentiation after synaptogenesiss
- target cells secrete neurotrophic factors
- neurons receiving insufficient neurotrophic support degenerate and die via apoptosis
27
Q
synaptic rearrangement
A
- after neuronal populations are established, trophic interactions continue to modulate synaptic connections
- trophic interactions ensure that each target cell is innervated by the right number of axons and that each axon innervates the right number of cells
- best understood in PNS
28
Q
functions of neurotrophins
A
- survival of a subset of neurons
- formation and maintenance of appropriate numbers of connections
- elaboration of axonal and dendritic branches to support connections
29
Q
Nerve growth factor
A
- first characterized, best studied
- acts on a few specific populations of peripheral neurons
- neuronal death in absence
- survival of more with excess
- presence and production in target cells
- NGF receptors in innervating nerve terminals
- DRGs respond to all, sympathetic ganglia
30
Q
some neurotrophins
A
- BDNF
- NT-3-nodose ganglia
- NT-4/5
31
Q
neurotrophin receptors
A
- Trk
- p75
32
Q
Trk
A
- family of receptor tyrosine kinases
- each binds to a distinct subset of neurotrophins
- all have high affinity for cleaved neutrophins
33
Q
p75
A
- can be activated by all neurotrophins
- high affinity for unprocessed, low for processed
34
Q
neurotrophin signaling
A
- activation of each class trigger distinct cascades
- variety of cascades can be activated by each class of receptors
- cell survival or death
- cell and process growth or differentiation
- activity dependent synaptic stabilization or elimination
35
Q
neutrophilic interactions depend on
A
-neurotrophins secreted from targets, receptors on neuron, intracellular cascades
determine-number of neurons, shape, patterns of connections
