Lecture 28- Glial development I Flashcards
What are glia?
• Essentially a catch-all category for more or less everything in the nervous system excluding neurons • Glia are an extremely diverse set of cells: • Different developmental origins • Different functional roles • Diverse morphologies and profiles of gene/protein expression
What is the percentage of glia in the brain of evolutionarily different organisms?
-With increase in size and complexity of nervous system comes a huge increase in the % of the brain made up of glia -nematode: few -drosophila: 25% -mouse: 65% -human: 50-90%
What are the types of glia?
1.CNS: • Astrocytes • Oligodendrocytes • Microglia • Radial glia • Ependymal cells 2.PNS: • Schwann cells • Satellite cells • Olfactory ensheathing glia • Enteric glia
What are some characteristics of the Schwann cells?
-PNS -surround axons in PNS -are responsible for myelination of peripheral axons -participate in repair process after injury
What are some characteristics of Oligodendrocytes?
-CNS -myelinate CNS axons -provide structural framework
What are some characteristics of Astrocytes?
-CNS -maintain blood-brain barrier -provide structural support -regulate ion, nutrient and dissolved gas concentrations -absorb and recycle neurotransmitters -form scar tissue after injury -regulate blood flow -regulate synpatogenesis
What are some characteristics of Microglia?
-CNS -immune cells of the CNS -remove cell debris, wastes and pathogenes by phagocytosis -present antigens to T cells in disease -participate in synaptic pruning? (maybe) -macrophages of the brain
How do oligodendrocytes make the myelin sheaths on axons?
-the oligodendrocytes will extend processes that will wrap around an axon to insulate -all oligodendrocytes are myelinating
What are two types of Schwann cells?
-Myelinating (large diameter axons) -Non-myelinating (small diameter axons!Remak bundles)= these provide protection to the axons
What can the Schwann cell do when there is an injury?
-Can become phagocytic in presence of injury
How do Schwann cells myelinate the PNS axons?
-secrete components of the basil lamina and extracellular matrix
What are the most abundant cells of the human CNS?
-astrocytes
What are the two types of astrocytes?
-fibrous astrocytes (white matter) -protoplasmic astrocyte (grey matter)
What are the roles of of astrocytes?
- Express high levels of glutamate transporters: prevent excessive glutamate build-up around synapses
- Similarly, buffer extracellular K+ to prevent it interfering with propagation of action potentials
- Link synapses with blood vessels to couple neuronal activity with regional blood flow/glucose delivery
- one of the main roles= have glutamate transporters= clean up the neurotransmitter so it doesn’t become toxic
- also clean up K+ -link synapses to blood flow= some of the processes signal to blood vessel to increase blood in the region etc.
- fMRI really looks at the activity of the astrocytes= the blood flow at the receiving end of the astrocytes
What is the tripartite synapse?
- Astrocytes also believed to form part of the “tripartite synapse”
- Astrocytes have processes adjacent to synapses • Upon neurotransmitter release astrocytes also activated (as evidenced by increased intracellular Ca2+ levels)
- This in turn can lead to release of neuromodulatory substances such as glutamate, ATP and adenosine
- when synapses release transmitter= astrocytes can respond, can regulate the blood flow an dcan release ATP and adenosine
- modulate synaptic function
What was the experiment with injecting human astrocytes into mice?
-took out human astrocytes and injected to mice= they were better in learning, memory than the control mice that had mice astrocytes injected =suggests the astrocytes are important in learning -• Engraftment of human astrocytes into mice has recently been shown to improve their performance in some learning tasks • How much of our cognitive processing is due to glia?
What are some more roles for microglia?
• Also first systematically described by Pio del Rio Hortega • Described as “microglia” to distinguish them from “macroglia” (astrocytes) –physiological role= phacoytosis of debri, dead cells etc. -microglia swicth between two states, resting and active (ameboid) state= the one where phagocytosis happens -• Major physiological role is the phagocytosis of cellular debris and pathogens • Are thought to be the antigen presenting cells of the CNS (interact with T-cells in injury) -• Highly reactive to disruptions to normal homeostasis or injury, however:
What are the two states of the microglia?
- Ramified 2. Amoeboid
What are the stages in neural cell birth?
- Pulse-chase labelling studies using tritiated thymidine or retrovirus to birth date cells led to the model of sequential specification of neurons, then glia
- seems that there are stages in development when different cells are born
- first neurons hen glia
- neurogenesis, then astrogliogenesis and then oligodendrogenesis
How does the shift from specification of neurons to glia occur?
- This shift is due to changes in both extracellular gliogenic signals and the instrinsic properties of the neural stem cells
- the shift is due to the environement of the brain -intrinsic change in the stem cells in the brain, at later stages= only glia born
What is the overly simplistic model for the development of specification of neurons vs glia?
-early stages= neurogenic stage, later gliogenic stage
What is the current model of the specification of neurons vs glia?
- Current model more complex, however, and needs to take into account a number of different stem cell and progenitor populations
- this is the total model, do not have to remember this in detail
- even early on get glial progenitor cells
- at first neural stem cells giving rise mainly to neurons, later both neurons and intermediate prglial progenitor cells and later shoft to the glial only
What is the rest of the lecture about?
-generation of astrocytes and microglia
What do astrocytes arise from?
- Astrocytes thought to arise directly from radial glial cells during development
- radial glial cell gives rise to astrocytes
Where in the CNS does the specification of astrocytes occur?
Specification of astrocytes occurs in multiple CNS regions (both dorsoventral and rostrocaudal)
-astrocytes are developed by each level of the developing spinal cord
When does the specification of astrocytes occur?
The specification of astrocytes overlaps both spatially and temporally with generation of neurons.
How can you see the specification of astrocytes from multiple dorso-ventral domains and what does it mean?
-This specification of astrocytes from multiple dorso-ventral domains can be seen using a genetic fate mapping strategy -shows that astrocytes are given rise to by every level of the neural tube -thus it is not the region of the spinal cord that determines if it is an astorcytes or neuron
What determines the specification of astrocytes vs a neuronal fate?
- The extrinsic factors that promote astrogliogenesis are poorly defined, but several signalling systems have been identified:
1. • Delta-Notch pathway
2. • LIF/CNTF/CT-1 -JAK/STAT pathway
3. • BMP-SMAD pathway
What is the role of delta/notch pathway in determining the astrocyte fate?
-did this pathway already -• Lateral inhibition via the Delta/Notch system partially responsible for setting up a mixed population of neural/astrocyte progenitors -Proneural transcription factors including: Neurogenin,Mash1 and! Olig2, promote Jagged/Delta expression -This in turn activates Notch in adjacent cells -Notch in turn inhibits proneural transcription factors and increases expression of Hes and NFIA (1 in there) to maintain cells as progenitors/astrocytes
What does Hes do?
Hes= keep cells in immature state, prevents from becoming a neuron
What does NFIA do?
-one of the ways notch makes astrocytes occur is by activating the NFIA • NFIA (induced by Notch) is an important promoter of astrogliogenesis • Usually induced around the time that astrocytes start being generated • siRNA knockdown of NFIA gene in developing chick spinal cord leads to loss of GLAST expression (astrocyte marker) -the experiment showing this: look at the picture!
How do the •LIF/CNTF/CT-1- JAK/STAT and BMP-SMAD pathways contribute to astrocyte specification?
- Lif induces JAK/STAT to go inti the nucleus and change gene transcription, turns on astrocyte genes
- BMP binds and activate SMAD that then affects gene transcription as well
- These factors lead to activation of astrocyte gene promoters, which become accessible through Notch
- mediated changes in DNA structure
When is it easier for cells to become astrocytes rather than neurons?
- cell become more capable of become astrocytes rather than neurons when the genes for astrocytes are not methylated any longer= so easier to access by the pathways
- this happens later in embryonic development
What is the composite model for astrocyte specification?
- Composite model has Notch and JAK/STAT pathways interacting with transcription factors and chromatin state to induce astrocyte specification
- these pathways are active once you have developed neurons
- neurons produce jagged and delta and lif CNTF and CT1 all of which activate the pathways leading to astrocyte specification
- model of lateral inhibiton= the cell fated to be neurons will signal surrounding cells to become astrocytes
Are microglia very different from other cells in the nervous system?
-yes very different to the other cells of the nervous system -they look different and are an immune cell type
What’s been the burning question about microglia for a while?
• Embryonic origins of microglia hotly debated for a long time • Neuroectodermal origins? • Generated by monocytes migrating into the CNS during development? • Constant exchange with macrophages in the peripheral blood? -these are the theories that were considered for microglial origin -macrophages and microglial are super closely related, hard to tell apart
What is the origin of the microglia?
-yolk sac origin
How did they discover the origin of the microglia?
- discovered in 2010 using genetic fate mapping techniques in mice -embryonic microglia detectable by CX3CR1 expression from E9.5:
- transgenic mice, looking at where the microglia are coming from
- the mesenchymal cells migrate to the developing brain
- they also put in a dye into cells of the yolk sac and saw if these move into the embryo
- Activation of lacZ reporter expression in yolk sac cells at E7.25 resulted in lacZ+ microglia in the brain at E9.5= proof of the microglial origin
- coming from the developing yolk sac -label some of the cells of the yolk cells blue, they will remain blue
- then see that the embryo has them in so the microglia are likely derived from the yolk sac
- hemopodic stem cells of the yolk sac are the origin!
Do people get microglia (macrophages) from the periphery during their lifetime? How was this anwered?
-Using irradiation experiments in newborn mice and parabiosis experiments to replace circulating myeloid cells, Ginhoux and colleagues demonstrated that >95% adult microglia remained host-derived –the experiment= shows that the macrophages from the blood circulation show that they don’t go into the brain from the periphery, instead have a self-replenishing population in the brain -These experiments, along with observations that the microglia were highly proliferative through life, show that microglia are derived from primative yolk sac myeloid progenitors that form a self-replenishing population in the brain
Summary?
• Glia are a large proportion of the brain in larger/more complex animals • Oligodendrocytes and Schwann cells: Myelinate/ ensheath axons to increase the speed and efficiency of conduction • Astrocytes: Buffer extracellular neurotransmitter and ion concentrations as well as linking neuronal activity to blood flow • Microglia: The “macrophages of the CNS” • Developmentally, neurons tend to be born prior to glia, though in reality there are multiple overlapping progenitor populations • Shift from neurogenesis to astrogliogenesis occurs: • Due to lateral inhibition from neurons via Delta/Notch • Through astrogliogenic signals including CNTF and the BMPs • These converge to induce expression of pro-astrocyte genes such as NFIA and GFAP • Microglia are myeloid cells that migrate from the yolk sac into the brain during embyronic development (microglia are important in the refinement of synaptic connections too, mop up the unneeded synapses)
