Lewin - Neuron death, growth, and neurotrophins Flashcards
What model system was used to study naturally occurring cell death in the dorsal root ganglia (DRG)?
A. male mice
B. female mice
C. chick embryo
D. drosophila
C. chick embryo
What was found via chick embryos regarding cell death and the DRG?
- The amount of target tissue influences neuron survival
- there was less cell death in ganglia that are innervating limbs
What is the neurotrophin hypothesis?
- theres a factor that neurons must take up to survive
- there is a limiting amount of this factor –> some will live, some will die
- match innervating cells to size of the target tissue
- the number of growth factors produced by the cell will determine if it lives or dies
What is Nerve Growth Factor (NGF) and how was it discovered?
- a target-derived soluble factor that can support neuron survival
- implanted tumor cells into the chorion allantoic membrane - compared when tumor cells were placed in embryo (only simulated cell growth in side it was implanted) or directly in the membrane (stimulated cell growth everywhere)
NGF was determined to be some kind of protein. What was used to better understand the nature of this factor?
- snake venom was used to exclude that the factor was nucleic acid (snake venom digests nucleic acid)
- can also use mouse saliva to purify the factor
Neurons can survive without NGF.
A. true
B. false
B. false
Neurons can survive in very low concentrations of NGF, but can’t survive without it
What of the following are true about NGF? (more than one may be true)
A. it is a dimer
B. active form is 15kD Beta-NGF dimer
C. NGF is synthesized as pro NGF
D. NGF serves as a survival factor for a large proportion of peripheral neurons
B. active form is 15kD Beta-NGF dimer
C. NGF is synthesized as pro NGF
D. NGF serves as a survival factor for a large proportion of peripheral neurons
NGF is the only growth factor.
A. true
B. false
B. false
there are 4: NGF, BDNF, NT-3, NT-4
What is TrkA?
- a membrane protein which, when comes together w another TrkA subunit, becomes active an phosphorylates itself
- is a receptor for NGF anf NT3
- has a high affinity (doesn’t need a high concentration)
What is P75?
- a protein that can bind to all GFs, but has a low affinity (requires a high concentration)
- with NGF –> is a survival enhancer
- with proNGF –> promotes cell death
What receptor does BDNF bind to?
TrkB only
What receptor does NT3 bind to?
Trk A,B,C, but has a high affinity to TrkC
What is the interaction between Neurotrophin and Trk receptor?
- when Trk binds to the ligand it dimerises and the receptor can auto-phosphorylate
- these phosphate residues make the proteins recognizable –> signal cascade of activation
- each receptor has a different combination of phosphate residues –> allows for specificity and selectivity
What receptors are involved in cell survival?
A. TrkA
B. TrkB
C. TrkC
D. P75
A. TrkA
B. TrkB
C. TrkC
What receptors are involved in cell death?
A. TrkA
B. TrkB
C. TrkC
D. P75
D. P75
What is apoptosis?
- an active mechanism that requires new gene transcription and protein synthesis in order to deliberately kill the cell
- requires signalling
What is necrosis?
- non-actively regulated cell death due to cell damage (pathological cell death)
- dying cells swell and become lysed
How can apoptosis be delayed?
by blocking protein synthesis
-ex. presence of cycloheximide blocks -NGF –> neurons can survive
What are caspases?
- a family of proteins that initiate and promote apoptosis
- there are two types: initial cascade, and executionary cascade
What is CED3?
- a mutagen in nematodes that leads to cell death
- similar genes are highly conserved across evolution
In mammals what are the regulators involved in apoptosis?
- BaX = pro apoptosis
- BCL-2 = anti-apoptosis. Activates mitochondria to become more active and produce more ATP (prevents Cyt C from activating)
- Cyt C = initiates caspase activation
How is Trk signalling linked to apoptosis?
Trk binds to the ligand (phosphorylates) –> binds protein –> CREB can bind to the complex –> enters the nucleus (after phosphor.) –> enhanced BCL-2 transcription which blocks apoptosis
How is MAPKinase signalling linked to apoptosis?
through phosphorylation and mitochondria, this pathway blocks the activation of Cyt C and delays apoptosis
-NGF with ERK leads to…
A. cell death
B. no cell death
B. no cell death
ERK bipasses the effect of -NGF
NGF + JNK leads to…
A. cell death
B. no cell death
A. cell death
JNK leads to apoptosis
What are two roles of NGF?
- prevention of cell death (MAPK, ERK)
- promoting neurite outgrowth (P13K/Act pathway)
Based on mouse KO studies, it was found that…
A. Bax is required for apoptosis
B. Bax prevents cells from undergoing apoptosis
C. in the presence of Bax and NGF, cells grow normally
D. signaling happens at neurite endings
A. Bax is required for apoptosis
C. in the presence of Bax and NGF, cells grow normally
D. signaling happens at neurite endings
Neurotrophins are not required for long distance growth but are required for fine tuned innervations and local branching.
A. true
B. false
A. true
Which of the following are involved in local branching?
A. NGF
B. NT3
C. NT4
D. CREB-mediated gene
A. NGF
B. NT3
Which of the following are involved in long range axon growth?
A. NGF
B. NT3
C. NT4
D. CREB-mediated gene
D. CREB-mediated gene
What type of sensory neurons do the first cells that arrive to the DRG give rise to?
-the first cells give rise to postmitotic cells that divide very few times –> give rise to large mechanoreceptors
What type of sensory neurons do the late migrating cells that arrive to the DRG give rise to?
-the late cells divide and proliferate many times and give rise to large and small nociceptors
The expression of different neurotrophic receptors will determine cell type. In what cells are TrKB and TrKA present in?
- TrKB is present in all proliferating cells
- TrKA is present in all postmitotic cells
NTFs are involved in defining the identity of neurons.
A. true
B. false
A. true
-all mechanosensory cells are dependent on embryonic NGF
NGF is the most present neurotrophin when it comes to synaptic plasticity.
A. true
B. false
B. false
BDNF is the most present NT when it comes to synaptic plasticity.
What is the role of NGF in pain and inflammation?
- NGF induces pain
- it is an acute inclusion of inflammation –> leads to hypersensitvity of nociceptors
- by making inflammation in the skin - production of NGF is increased
