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Neural determination

Terms in this set (32)

How can the birth date of a neuron be identified?
Using thymidine analogues e.g. tritiated thymidine (3HT)
Describe the activation-transformation model of AP patterning.
1. Activation
- Anti-BMPs induce the expression of anterior Hox genes (amongst other genes)
- So as soon as a cell is specified to become neural => it is anterior

2. Transformation
- Posterior Hox genes are turned on/ expressed due to the action of caudalising agents
- E.g. RA binds to RAR => translocates into the nucleus => binds to RAREs => regulate the transcription of posterior Hox genes, amongst other things
Describe the induction of neural tissue in vertebrates.
1. Expression of anti-BMPs e.g. Chordin and Noggin from the notochord
2. Anti-BMPs act to inhibit the action of BMPs
3. Allows the expression of proneural genes

=> works alongside FGF
Describe the induction of neural tissue in invertebrates.
Invertebrates express Sog (equivalent to anti-BMP)
Sog inhibits the expression of Dpp (equivalent to BMP) => allows expression of neural tissue
Describe DV patterning.
Notochord is below the neural tube - secretes anti-BMPs and Shh
1. Dorsally
- High BMP
- Low Shh
=>

2. Ventrally
- Low BMPs (due to the anti-BMPs)
- High Shh
=> motor neurons expressed


*All due to the expression of Class I and Class II Hox TFs
- These are distinct from the TFs involved in AP patterning
- But from the same family

Class I - turned off by Shh
Class II - turned on by Shh

=> the expression of the combinations of Class I and Class II transcription factors determines the fate of the neuron on the DV axis
How can motor neurons be induced ectopically?
Can be induced by exposure to a bead soaked in Shh

Can also be induced by exposure to a transplanted notochord
Activation-transformation model.
**Idea that all cells express anterior genes => posteriorising tissue comes later by the action of caudalising factors

=> this is the model behind AP patterning


1. Activation
- RA is expressed along the length of the notochord - expressed highest at the posterior end
- In response to the anti-BMPs => cells express anterior Hox genes

2. Transformation
- In presence of high concentrations of RA (or other caudalising factor) => the anti-BMPs act to produce
- RA combines with cytoplasmic RAR in the neuroectodermal cells
- RAR then crosses the nucleus and upregulates the expression of RAREs
Describe inside-outside patterning in mammals.
...
What types of patterning do we have in mammals?
1. AP patterning
- Governed by Hox genes
- As per the activation, transformation model
- RA and FGF are the caudalising agents

2. DV patterning
- Also governed by Hox genes (class I + class II)
- Expression of Hox genes is influenced by Shh
- The pattern of Hox gene expression determines the fate of the neuron

3. Inside-Outside
- To do with histogenesis - first born neurons make up the inner layers of the cortex, later born neurons make up the outer layers of the cortex
- RA also has some influence - later born neurons change their fate in response to RA expressed by
What are the two roles of RA?
1. AP patterning
- RA is a morphogen
- Sets up a gradient => high RA at posterior
- It is a caudalising agent

2. Cell fate in terms of inside -outside
How does asymmetry arise?
1. Clockwise beating of the cilia
2. Leads to an increase in TGF-β on the left side
What are TGF-β proteins?
- These bind to the TGF-β receptor to initiate a downstream cascade that inhibits the transcription of Sox2 and other neural transcription factors => so that the cell becomes epidermal
- An example is BMP4
- They are inhibited by anti-BMPs e.g. chordin
What is chordin?
- Binds to TGF-β proteins to prevent their action
What are the trophic factors?
E.g. nerve growth factor
E.g. BDNF

- Inhibits the always-poised apoptosis pathway => in the absence of the trophic factors, the apoptosis pathway ensues
=> the trophic factors are required throughout the life span of a neuron
Describe the apoptotic pathway.
Involves the activation of highly conserved caspase proteins => chew up other proteins
How does the nervous system ensure that there are always only the appropriate number of input neurons?
- Neurons compete with each other for trophic factors
- Only neurons receiving the appropriate number of trophic factors will survive
Describe how cell specific fates are achieved in the invertebrate?
Neuroblasts that have delineated from the neuroepithelium give rise to GMCs

The fate of the GMC is determined by:

1. Temporal identity genes
=> when they arise from the neuroblast
=> they inherit the genes expressed by the neuroblast at the time of division

Hb -> Kr -> Castor -> Pdm


2. AP Hox genes (Hox1, Hox2 etc) and DV Hox genes (ind, msh, vnd)
- Each neuroblast has a specific expression of Hox genes corresponding to its particular position
=> establishes positional identity within the neuroectoderm


**The first GMCs tend to become motor neurons e.g.
Nb1-1 ----> GMC ----> aCC (motor neuron)

**The first GMCs tend to give rise to motor neurons with long projection axons
**The last GMCs tend to give rise to to interneurons with shorter axons
How many ommatidia does the Drosophila retina have?
~800
Describe the development of the Drosophila retina.
Development of the Drosophila retina:
1. The first cell to develop (R8) expresses Ato => under the control of the Notch pathway (i.e. it suppresses the development of the surrounding cells by lateral inhibition)
2. The R8 cell expresses EGF
3. EGF binds to EGFR and initiates the development of R2 and R5
4. Sequential development of the remaining cells
5. The last cell to develop R7 has an interesting mechanism


R7 mechanism
1. R7 expresses the RTK, sev
2. R8 expresses Boss ligand (Bride of Sevenless) => boss activates Sev
3. Downstream signalling cascade involved in the determination of the R7 fate
What are the cells of the Drosophila retina that are of most interest?
R8 = first to develop
=> encodes the blue photoreceptor

R7 = last to develop
=> encodes the UV photoreceptor
What is the phenotype of the Sev mutant?
UV blind
What is the Boss mutant?
UV blind
What two phenotypes lead to a UV blind mutant?
Boss = bride of sevenless
Sev = sevenless
What is the morphogenic furrow?
Wave of development that passes across the Drosophila retina
What are the different organising centres in the developing vertebrate brain?
1. The floor plate
- Secretes anti-BMPs and Shh
- Determines the fate of motor neurons (DV axis)
- And also the AP axis

2. The roof plate
- Expresses BMPs

3. The midbrain hindbrain (MHB) region
- Organising centre characterised by the boundary between Otx2 and gbx2
- Otx2 => specifies the forebrain
- gbx2 => specifies the hindbrain
What is the role of otx2?
OT => X2

**Forebrain is OT = Oxford train i.e. the forebrain has to think about what train it is => complicated
What is the role of gbx2?
GB => X2

**Hind brain is GB = Great Britain i.e. the hindbrain is primitive => only knows what country the train is in!
What is the Q fraction? What does it determine?
Q fraction = the proportion of daughter cells becoming post-mitotic

> 0.5 => population declines
< 0.5 => population grows
Where do the GABAergic neurons arise during neural development?
- The neuroepithelium below the cerebral cortices only gives rise to glutamatergic neurons

- GABAergic neurones are generated adjacent the basal ganglia
What is the sub ventricular zone?
...
Where are the adult neural stem cells located?
1. Ventricular zone
- Inner most layer surrounding the lumen of the neural tube
- Gives rise to more cell types

2. Subventricular zone
- 2nd layer surrounding the ventricular zone
- Recently discovered
- Consists of neurons derived from the ventricular zone that are undergoing further rounds of cell divison
What is notable about the development of the mammalian brain
- Massive expansion of the neocortex
- Enabled by the ventricular zone
- And also by the newly discovered subventricular zone
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