Neurogenesis Flashcards
Stages of neurogenesis
birth, migration, differentiation
Where does neurogenesis occur?
It occurs at
the ventricular surface of
the developing brain
During early develop this region is very thin
Ventricular zone – contacting ventricle
Marginal zone (dorsal)
Where are neural progenitors?
Neural progenitors are in
the ventricular zone.
Progenitor cell for
neurons and astrocytes of
CNS
Known as radial glial cells
What are the steps of neurogenesis?
- Radial glial cell extends process to reach towards the pia at the surface of the brain
- Interkinetic nuclear migration – DNA is replicated
- Radial glial cell retracts its apically extending arm
- Cell division
- Migration of neuroblast from ventricular surface
What is 1-3 interkinetic
nuclear migration?
Process by which the nucleus of a radial glial cell migrates away and back towards the ventricular zone.
Necessary for DNA replication and ultimate cell division.
Describe symmetrical division
Happens early in development
Expands progenitor population
During symmetric divisions no neuroblasts are formed
Describe asymmetrical division
Happens later in development
Maintains progenitor pool size
Produces one neuroblast and one progenitor from each division
Majority of neocortical neurons born between 5 weeks and 5 months
Peak neurogenesis rate: 250,000 new neurons per minute
Schematic of the development of the
embryonic neocortex
- VZ – ventricular zone
- iSVZ – inner subventricular zone
- oSVZ– outer subventricular zone
- IZ – intermediate zone
- CP – cortical plate
- MZ – marginal zone
- aRG – apical radial glial cells
- bRG - basal radial glial cells
- IP – intermediate progenitor
Subventricular zone
Specific to primates
Second layer of proliferative progenitors
Gives rise to upper cortical layers
Hypothesized to increase connectivity between diverse neural areas through bridging neuronal projections that concentrate in the upper layers
What cells maintain
the ability to divide?
Daughter cells from an asymmetric division will
never divide again
Some progenitor cells are maintained into
adulthood
Vast majority of neurons you are born with are
what you have to work with your whole life
Stem cells are a new and fascinating area of investigation
Originally thought no new neurons were born after adulthood
The discovery of
adult
neurogenesis
1965: Altman and Das provided evidence that adult neurogenesis occurs in mammals
1983: Goldman and Nottebohm showed adult
neurogenesis in canaries
Radiolabeled thymidine (T) incorporates into DNA during replication. .Slice brains and expose to film. Radiation will work like light to create “exposure” of the film
1996: Kuhn, Dickinson-Anson, and Gage showed adult neurogenesis in mammals again, this time using BrdU.
Can be incorporated instead of thymidine into replicating DNA
How does BrdU work?
Uridine analog
Add BrdU during fixed time period
Animals – inject
Cells – bath
BrdU incorporates into DNA during replication as a thymidine analog
Antibodies again BrdU for immunolabeling of DNA that includes BrdU
Nobel Prize in chemistry 2022: Click chemistry
Using EdU instead of
BrdU
Modernized DNA labeling
Copper catalyzes binding of substrates.
Fluorescently label DNA that has EdU incorporation.
Neurogenesis in the human brain
Postmortum brains of humans were analyzed
Nuclear bomb tests released Carbon-14 into the
environment, essentially labeling biological materials
from the fallout
Using carbon dating, Spalding, Frisèn, and colleagues
found cortex from these people did not show labeling
but hippocampus did.
700 neurons are turned over in the hippocampus each day (~2%/year)
DNA transcribed to RNA in nucleus
RNA spliced and exported to cytoplasm
How do cells know whether to be
a progenitor or a daughter?
RNA translated to protein via ribosomes
Ribosomes seated on Rough ER
Protein is packaged and actively moved to correct location.
During division, asymmetric compartmentalization
of particular proteins (and probably RNAs) leads to
fate determination
Transcription, translation, and compartmentalization govern
One radial glial progenitor can produce neurons and glia
Cell migration in the developing cortex
Once a neuroblast is born, how
does it get where it needs to go?
Cortical migration from ventricular zone of dorsal telencephalon to cortex which gives rise to pyramidal
neurons and astrocytes.
Tangential migration from ventricular zone of the ventral telencephalon to cortex which gives rise to inhibitory interneurons and oligodendrocytes
Migration of neuroblasts occurs along radial glial fibers
Cortical migration
Have a leading process, nucleus, and trailing process
Nucleus is pulled to leading process as it migrates up radial glial
fiber to cortex
Involves the Subplate:
Transient structure
Contains a variety of neurons
Most are glutamatergic
Responsible for early motor behavior
Role in defining cortical regions for sensory processing
First cells to migrate from the ventricular zone are the subplate cells
Activity onset 9-10 weeks post-conception in humans. Thickest 28-34 weeks post-conception. Most active fetal brain
area. Subplate is gone by 3 months post-birth
Inside out cortical assembly
Next cells to migrate make up layer VI
Then layers V,IV,III,II, I
Inner layers are set up first and cells migrate past them to form the next layer
Mutations can disrupt this assembly: Reelin mutant
Specific to late born cortical neurons
What does Reelin do?
An extracellular matrix glycoprotein.
Protein bound by oligosaccharides
Secreted by Cajal-Retzius neurons in the marginal zone
Binds to very low density lipoprotein receptor (Vldlr) and Apoer2
Vldlr – reenlin binding is a stop signal for migration
Apoer2 – reelin binding is a go signal for migration
How was reelin discovered?
Spontaneous mutation in a mouse line
Named reelin because of its abnormal gate.
Identified in Edinburgh in 1951
Histopathological analysis showed cortical laminar organization deficit
Abnormal reelin expression linked to a variety of psychiatric disorders: Schizophrenia, autism, Bipolar disorder, Alzheimer’s.
Whether there is a causal link is unclear.
Tangential migration
Gives rise to inhibitory interneurons and oligodendrocytes
Does not use radial glia
Neurons maintain a stellate shape and are highly individually motile
Also some evidence for chain migration
Migrate from the ganglionic eminences
Medial ganglionic eminence
Produces GABAergic interneurons that migrate to cortex
Lateral ganglionic eminence
Produces GABAergic interneurons that migrate in the rostral migratory stream to the olfactory bulb
Caudal ganglionic eminence
Also produces inhibitory interneurons
that migrate to cortex
Occurs immediately following neural precursor (neuroblast) migration
Neuronal differentiation
Layer IV neurons differentiate before Layer III neurons migrate through.
Stepwise: Neurite outgrowth, Axon and dendrite specification, Target selection and stabilization, and Synapse formation.
Differentiation is regulated by intracellular and extracellular signals.
Cultured hippocampal neuron after 8 days in vitro (DIV) expressing green fluorescent protein (GFP)
Radial Unit hypothesis
The idea that progenitor cells in the ventricular zone give rise to columns of cortical neurons with connected fates
This would mean that a cortical ”protomap” exists in ventricular zone
1/3 of all neurons do not migrate up radial glia
Transcriptional patterning of
cortical areas
profiles
Neurons in discrete cortical regions have transcriptional
Emx2 and Pax6 example
* Anterior cortex expresses Pax6
* Posterior cortex expresses Emx2
* This is essential for cortical patterning
Altering expression alters cortical patterning
Emx2 mutant
* Expand motor and reduce visual. Somatosensory moves
posterior
Pax6 mutant
* Expand visual and reduce somatosensory and motor. Anterior shift of auditory and somatosensory
Normally, LGN of thalamus projects to visual cortex
What happens if you eliminate LGN input?
Projections also help to pattern the cortex
Input is clearly necessary for cortical differentiation
Reduce the size of visual cortex
Arrows point to the edges of visual cortex in primate with and without LGN input
Typically ventral posterior thalamus projects to somatosensory cortex
In rats, somatosensory cortex is arranged in “barrels”
Barrels correspond to whisker fields
Rat cortex to address the effect of innervation on cortical patterning
Cortical transplants address
sufficiency
In rats, thalamic fibers do not enter cortex until after birth
Pealed off somatosensory cortex (area 3) and replaced it with visual cortex (area 17)
Transplanted visual cortex develops barrels
Evidence that cortical architecture can be shaped by thalamic projections
