Neural Stem Cells Flashcards
What is another name for neural stem cells?
Neuroepithelial cells
What do NSCs asymmetrically divide into later?
One self-renewing NSC
One neurone
What else can neural stem cells generate?
Intermediate progenitors (transit amplifying cells)
Which can then either make neurones or glial cells
Give examples of glial cells
Oligodendrocytes
Astrocytes
Microglia
How long do stem cells live?
For the lifetime of the organism
Which germ layer does the nervous system develop from?
Ectoderm
Where do the signals come from that induce ectoderm to differentiate into neural plate?
Node or Organiser region = mesoderm derived
Where is the node/organizer region found?
Top of primitive streak
What signals from organizer/node induce neural tissue?
Fibroblast Growth Factor (FGF)
Transforming Growth Factor Beta (TGFb)
What happens to the neural plate later in development?
If folds up to form neural TUBE
Neural tube begins to extend forming anterior-posterior axis (head to tail elongation)
What can neuromesodermal progenitors (NMP) give rise to?
Spinal cord neural progenitors
Mesodermal progenitors
What are the two markers used to differentiate neural progenitors and mesodermal progenitors?
Sox2 marks neural progenitors
Brachyury (Bra) marks mesodermal progenitors
What is neurulation?
When neural plate folds to make neural tube
What gives rise to CNS?
Proliferative ventricular layer gives rise to the CNS
What gives rise to PNS?
Nerual crest cells migrate from dorsal neural tube and give rise to PNS
Including ganglia in the head and gut
Which part of the spine have cells doing the most proliferation?
The cells closest to the inner spine in the ventricular layer
Apical surface faces the centre of the neural tube
What do neural stem cells under go as they progress through cell cycle?
Interkinetic nuclear MIGRATION
Descibe where neural stem cells are as they go through the cell cycle
As they proliferate, move towards basal side of neural tube
When they differentiate = migrate outwards extending neural axis along the side
At S phase they reach the basal side, then return back to the apical side during G2
Finally returning to apical side at M phase
Axis of division is a specific was for asymmetrical division
Which zone are differentiated neurones found in?
Cortical plate / Marginal zone
What zone is expanded in humans?
Sub-ventricular zone
What regualtes NSC self-renewal?
Extrinsic signals such as, FGF, Wnt, IGF, and Notch pathway signals
What occurs in NSCs when Notch signalling is lost?
Cell cycle exit induced
AND
Premature neuronal differentiation
(in a wide range of animcal embryos and reigons of developing nervous system)
What mechanism does Notch signalling mediate?
Lateral inhibition
How does lateral inhibition work?
Neurons must decide whether to differentiate or stay undifferentiated based on the signals they receive from their neighbors.
Initially, neighbouring cells experience similar levels of Notch signalling.
When nascent neurons are in close proximity, they interact with each other. Nascent neurones express higher levels of Delta1, this increases Notch signalling in neighbouring cells
High Notch signalling represses neurogenin (proneural gene) = leading to reduced Delta1 expression.
Reduced Notch signalling in the newborn neuron and so increases levels of neurogenin and Delta1 in the nerones itself
What does having high levels of neurogenin do?
Proneural gene so more likely to differentiate into a neurone
What can cause bias of Notch signalling?
Orientation of NSC
This is because of differential inheritance of proteins localised at the apical side of the cell
What symptoms can loss of Notch cause?
Reduced proliferaiton of NSC reduces their pool
Failure of apical radial glial cells to generate intermediate progenitors and reduced neurone number (ref to image)
Expansion of human cortex further relies on proliferation of outer radial glial cells
What can happen during early development with viruses?
Viruses can infect the apical (ventricular zone) NSC because the CSF is exposed to env factors
Name two viruses that target aNSC?
Cytomegalo virus
ZIKA virus
What do cytomegalovirus and Zika virus have in common?
Both cross the placental barrier
Both ahve strong tropism for adult NSC
How does cytomegalovirus enter cells?
Via cell surface receptors
Such as integrin B and EGFR
How does Zika virus enter cells?
By degrading apical cell-cell adheren junctions
What is the mechanism of action of cytomegalovirus?
Down regulation of Notch1 receptor
Mislocalisaiton and degradation of Notch ligand Jag1
Degradation of Notch transcriptional target Hes1 by viral protein
What is the mechanism of action of Zika virus?
Non-structural Zika virus proteins = interfer with PKB-mTOR pathway
Impairing adult NSC growth and transition to intermediate progenitor generation
What does cytomegalovirus cause?
Congenital infection associated with hearing loss, microcephhaly and intellectual disability
What does Zika virus cause?
Reduced cell survival and proliferaiton
Prevovious neuronal differentiaiton with overal fewer neurones = leading to microcephaly and intellectual disability
What are adult NSC also referred to as and why?
Astroglial cells because they express
Glial marker = GFAP
NSC marker = Sox2
What does it mean by aNSC are often heterogeneous?
They can be in different states of actiivty or dormancy/quiescence
May have different roles in tissue homeostasis and in regeneration in response to injury
What cells do adult NCS give rise to?
Intermediate progenitor cells, which then generate neuroens OR glia
Where are adult NSC mainly located in humans?
Dentate gyrus of hippocampus = concerned with memory and learning
Lateral ventrical wall = provides new neurones that migrate to the olfactory bulb in most mammals
What are the functions of the places where aNSC are found?
Dentate gyrus of hippocampus = concerned with memory and learning
Lateral ventrical wall = provides new neurones that migrate to the olfactory bulb in most mammals
How are aNSC identified?
Label cells with BrdU, which is an analogue for base
When cell divides = dilutes BrdU because of semiconservative replication
If you see neurones with BrdU = they were made after giving mice BrdU
So must be aNSC but this it not fail proof
What is the aNSC NICHE?***
Located in complex celluar niches = lateral ventricle and dentate gyrus (hippocampus)
Niche exposes then to wide range of influences, which maintain these cells and regulate their activity
Includes feedback from differentiating progeny, signals and nutrients from associated blood vessels and the activity of mature neurones
How do the factors provide by the niche affect aNSC?
Causes differentiation towards cell fate lineages
How does carbon dating work for humans?
Carbon is taken into our bodies by our diet
The C birth dates cells based on the levels of C14 in DNA synthesized when a cell duplicates its DNA during S-phase
What evidence from carbon dating proves the existance of aNSC?
C14 levels in hippocampal neurones correspond to those at time of DEATH = suggesting they must be newly generated
Uniformly elevated levels of C14 in people born before tests began to further suggest rate of ault neuogenesis in hippocampus does not decline dramatically with age
How did they use cell type marker analysis to support adult neurogenesis?***
Presence of Immature Neuron Markers in Adults
Co-localization of Cell Cycle + Progenitor Markers
Spatial Location of the Markers
Quantitative Changes with Age or Disease
What evidence is there that HUMAN adult neurogenesis does not take place?***
Markers drop in adolescence, such as doublecortin (DCX)
Humans may stop neurogenesis earlier in life than other species, where is there is evidence for neurogenesis
Neurgenesis is not seen during disease, which is when it may be expected to occur
Opposing conclusions because of differences in
- Differences in tissue preservation
- Antibody specificity
- Subject age, disease state, or postmortem delay
Why may BrdU not be reliable indicator of HUMAN adult neurogenesis?
Only low dose BrdU was administered and only ONCE
Some background flowescence labelling in round cells have been detected in non-BrdU treated human hippocampus
Why may C14 carbon dating not be reliable indicator of HUMAN adult neurogenesis?
Birth-dating w C14 relies on isolation of neuronal nuclei using NeuN Ab
But subpopulations of oligodendrocytes and microgia can also express NeuN
C14 could also become incorporated into DNA of neurones through methylation or DNA repair independent of cell division = processes that have been shown to occur at high rates in the hippocampus
What are the advantages of single-nucleus RNA seq?
Can look at the whole fo the genome
What is Zhou et al’s conclusion on adult neurogenesis taking palce?
Function of adult human neurogenesis arises from unique properties of immature neurones
Not driven by generation of new neurones
Changing transcriptional landscape of immature neurones as we age = suggests change in cell function, niche interation and disease relevant disease
What did cultured surgical explants suggest about neurogensis?
Capacity to generate new neurones in adult human hippocampal tissue in vitro
What happens to immature neurones in Alzheimer’s?
Immature neurones in adults are present but are reduced (exhibit distinct gene expression)
