Axon Growth And Regeneration Flashcards
Name a local and distal effect of an extracellular growth cue binding to its receptor
Local: Cytoskeletal changes
Distal: Expression of transcription factors
Name the 3 types of extracellular cues guiding axon growth
Attractive, repulsive, promoting survival
State 4 ways in which the growth cone can respond to an extracellular growth cue
Change direction, collapse, stall, form a pre-synaptic terminal
Name the 2 main components of the growth cone
Sheet-like lamellipodia and finger-like filopodia
Describe the most important pathway in growth cone collapse
Rho to ROCK to LIMK to cofilin leading to actin depolymerisation and growth cone collapse
Name 3 signals promoting neuron survival
NGF, NT3, BDNF
Name 2 synaptogenic factors
Wnt family, neurexin
What does neurexin bind to on target cells?
Neuroligin
Name 2 long-range molecular growth cues
Netrin, neurotrophins
Describe the netrin gradients in the spinal cord
Netrin 1 has a steep gradient and is expressed by the ventral floor plate. Netrin 2 has a gradual gradient and is expressed by neural epithelial cells in the ventral two thirds of the spinal cord
Describe the effect of netrin gradients on commissural neuron growth
Commissural neurons in the dorsal spinal cord are attracted towards the ventral floor plate because of the netrin gradient and their deleted in colorectal cancer (DCC) receptors
Name at least 3 neurotrophins
Nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3, neurotrophin 4, neurotrophin 5
Which neurotrophin binds to the TrkA receptor?
NGF
Which neurotrophins bind to the TrkB receptor?
BDNF, NT4, NT5
Which neurotrophin binds to the TrkC receptor?
NT3
Describe the effect of neurotrophins binding to a Trk receptor
They cause dimerisation, leading to intracellular signalling via Rho GTPases and local cytoskeletal changes
Describe how NGF stimulates neuronal survival
It binds to TrkA, leading to dimerisation. The NGF-TrkA complex is endocytosed and retogradely transported to the cell body, setting off a signalling cascade which stimulates neuronal survival
How does dysfunctional APP affect Trk?
It leads to decreased delivery of Trk across the axon, as delivery is mediated by APP. This leads to decreased NGF signalling, less neurotrophic support, and neuronal death
Name 2 cell-associated positive growth cues
N-CAM, N-cadherin
Name the 2 subtypes of NCAM and their roles
NCAM-PSA - involved in early development and neuronal migration
NCAM-VASE - involved in late development and inhibiting the neuronal response to NCAM
Name the receptor NCAM acts on
Fyn-FGF receptor (as a cell-cell adhesion molecule)
Name 2 extracellular matrix associated positive growth cues and state which neurons prefer
Laminin and collagen - neurons prefer laminin
Name the receptor laminin acts on
Beta1 integrin receptor
Name 3 long-range negative growth cues
Netrin, semaphorins, slit
Which receptor combination makes netrin a negative growth cue?
DCC and Unc5
Describe the effects of semaphorin3 in the spinal cord
Seamphorin3 is a selective chemorepulsant in the ventral spinal cord - it repels NGF-responsive neurons with TrkA receptors, ensuring that they develop in the dorsal spinal cord. Conversely, NT3-responsive neurons expressing TrkC are not repulsed, so can enter the ventral spinal cord
Describe how Robo receptors control neural crossing of the midline
Slit is a midline chemorepellant which acts on Robo receptors and prevents them crossing the midline. For neurons to cross, their Robo receptors must be downregulated by commisureless (Com). Once they have crossed, Com is downregulated and Robo receptors prevent them from crossing back again
Describe how ephrin A controls development of the topographical map of the retina
There is an ephrin A gradient across the visual cortex. Temporal retinal ganglion cells have increased expression of the EphA receptor, hence their growth cone collapses in the anterior tectum with low levels of ephrin A. However, retinal ganglion cells express fewer EphA receptors, so can progress further into the posterior tectum, where their growth cone collapses due to a higher level of ephrin A
Name an extracellular-matrix associated negative growth cue
Chondroitin sulphate proteoglycan (CSPG)
Summarise why an axonal lesion in the CNS fails to regenerate
An axonal lesion disrupts the membrane potential, causing a Ca influx and activating kinases and intracellular signalling. Macrophages are recruited and astrocytes and microglia proliferate, releasing CSPGs and forming a glial scar. Myelinated fibres are disrupted, leading to RhoA release and growth cone collapse
Summarise why axonal lesions in the PNS can regenerate
NGF is secreted by Schwann cells and enters through the break in the membrane and is retrogradely transported to the cell soma. This activates transcription factors for pro-regenerative genes. NGF also increases CREB and decreases RhoA
Name 2 growth inhibitory signals secreted by oligodendrocytes and astrocytes
Nogo-A, MAG
Is NGF secreted in the CNS after injury?
Yes - by astrocytes and microglia - but the inhibitory signals are stronger than growth signals
Describe the method of action of chondroitin sulphate proteoglycans
They are secreted by astrocytes and act on PTP-sigma receptors and Nogo receptors to activate RhoA
Describe how oligodendrocytes inhibit neuronal regeneration
Injury to oligodendrocytes exposes myelin proteins - MAG, OMgp, and Nogo - which activate RhoA
Name at least 3 intrinsic cell signals which promote regeneration
Neurotrophins, IL-6, integrin receptors, retinoic acid, mTOR
Describe how IL-6 promotes regeneration
IL-6 is activated by inflammation and leads to formation of a Gp130-Jak2 dimer. This dimer phosphorylates STAT3 and activates pro-regenerative genes
Describe how neurotrophins promote regeneration
Neurotrophins act on Trk receptors and activate cyclic AMP. This leads to PKA phosphorylating CREB, activating pro-regenerative genes
Describe how retinoic acid promotes regeneration
It binds to the intranuclear retinoic acid receptor to promote intrinsic growth pathways and inhibit inhibitory pathways
State some regenerative possibilities for a supraspinal axon transection
Sprouting from lesioned axons to other supraspinal projections, sprouting to propriospinal relays, sprouting of unlesioned propriospinal axons, sprouting of remaining supraspinal axons, regeneration through the lesion
Describe how Nogo antibodies could improve recovery after spinal cord injury (Liebsher, 2005)
They have been shown to increase sprouting in animal trials, with some axons growing past the lesions, as well as decreasing growth cone collapse. Phase I trials have shown they are safe in humans
Describe how chondroitinase could improve recovery after spinal cord injury (Bradbury, 2002)
It could dissolve CSPGs and inhibit glial scar formation. It has been shown to promote axon growth past the lesion and improve locomotor function in rodents
State a disadvantage of cyclic AMP analogues and phosphodiesterase inhibitors
They lack specificity so have high toxicity
Describe how taxol could improve recovery after spinal cord injury (Hellal, 2011)
Taxol stabilises microtubules, decreasing growth cone collapse and decreasing glial cell motility, hence inhibiting glial scar formation. In rodents, it has been found to improve axon regeneration into the lesion and improve motor coordination
Describe how PTEN deletion could improve recovery after spinal cord injury (Liu, 2010)
PTEN inhibits mTOR, so removing it prevents mTOR inhibition. In animals, PTEN deletion has been found to increase corticospinal tract regeneration
Describe the role of histones in axon regeneration in the PNS
Following injury, NGF, MEK, and ERK are retrogradely transported to activate PCAF and promote histone acetylation. This promotes accessibility of transcription factors and access of pro-regenerative genes
Describe how PCAF overexpression could improve recovery after spinal cord injury (Puttagunta, 2014)
PCAF promotes histone acetylation and accessibility of transcription factors. In trials, PCAF overexpression has been found to allow axons to grow past a lesion site supported by astrocytes
Describe the role of histone deacetylase inhibition in promoting axon regeneration in the PNS
After injury, histone deacetylase is dephosphorylated, decreasing its activity so that histones remain acetylated and hence pro-regenerative transcription factors remain accessible
Describe how histone deacetylase inhibitors could improve recovery after spinal cord injury
HDAC3 inhibition could increase the accessibility of transcription factors for pro-regenerative genes - it has been shown to promote outgrowth of primary dorsal root ganglia neurons in animals, and is now in phase I human trials
