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Mechanisms of Brain Development > Week 4 > Flashcards

Week 4 Flashcards

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1
Q

Patterning along the AP axis. There are cards about the forebrain, midbrain and hindbrain developing in the telencephalon etc.

Which of the brain areas does:
a) Forebrain
b) Midbrain
c) Hindbrain
- develop into.

Going further, what do the 5 vesicles then go on to constitute specifically?

A

a) Forebrain:
- Telencephalon
- Dienchephalon
b) Midbrain:
- Goes straight to the Tectum and Substantis nigra
c) Hindbrain:
- Mesencephalon
- Myelcephalon

Telencephalon -> Cerebrum, hippocampus
Diencephalon -> Thalamus, hypothalamus, retina

Midbrian -> Substantis nigra

Mesencephalon -> Pons and Cerebellum
Myelcephalon -> Medulla

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2
Q

What are the two morphogens that influence AP axis development in drosophila

A

Bicoid
Hunchback

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3
Q

What is the relationship/difference between Gap genes, Pair-rule genes and Hox genes?

NOTE: These are present in the DROSOPHILA

A

Gap genes:
- Among the earliest genes expressed after fertilisation
- T.Fs that control the initial broad patterning of the embryo along the AP axis by dividing it into large segments
- Gap genes include hunchback and bicoid

Pair-Rule Genes:
- Activated in response to the pattern established by gap genes
- Further refine segmentation
- Expression occurs in ALTERNATING segments along the AP axis to ensure delineated segments
- Examples: ftz and eve

Hox genes:
- Specify the identity of segments along the AP axis
- Activated by gap and pair-rule genes
- Determine unique characteristics of each segment and guide development of structures
- Spatial arrangement corresponds to their position on the chromosome (co-linearity)

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4
Q

Hox gene mutants have dramatic phenotypes. What are they?

A

Segment duplication

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5
Q

What is a common feature of gap gene mutants?

A

Segment deletion

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6
Q

Hox genes are conserved in vertebrates.

How are they regulated?

A

Through early graded signals involving morphogens:
- Wnt
- RA
- FGF
- TGF-beta

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7
Q

These graded signals that influence Hox genes come from the mesoderm DURING neural induction

Match the function to the group of signalling molecules:

a) Induction of neural plate formation
b) Further graded posteriorising signals
c) Extreme anterior (forebrain) signal (needed to protect the anterior from the posteriorising signals)

  • Cerberus
  • BMP inhibitors
  • Wnt, Retinoic Acid (RA), FGF
A

a) BMP inhibitors
b) Wnt, RA, FGF
c) Cerberus

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8
Q

What is the retinoic acid signal pathway? (easy)

A
  • Fat soluble
  • Diffuses through membrane + acts on cytosol receptor
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9
Q

What is an exception to the Hox gene system? E.g., where is not patterned by this system?

A

The anterior brain!

  • A separate set of antagonistic T.Fs produce unique, overlapping domains that give regional identity
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10
Q

In drosophila, how to neuroblasts gain their identity?

A

Their position on the AP AND DV axes gives them their identity

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11
Q

In drosophila, each segment is divided into 2 subsegments, A and P cells. P cells express ‘engrailed’.

Interactions between A and P cells lead to 2 new signals being produced.

What are they and what do they do?

A
  • WG: Wingless
  • HH: Hedgehog

These signals diffuse to create local concentration gradients IN the segments

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12
Q

In the drosophila neural tube, the DV axis is set up by the production of 2 antagonistic signal proteins.

What are they, and what is the confusing T.F that influences them?
(whatare the homologues in vertebrates?)

A
  • DPP (the homologue of BMP)
  • SOG (homologue of chordin)

DORSAL is the T.F for ventral patterning

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13
Q

What are columnar genes?

And what are some of the T.Fs they encode?

A
  • Columnar genes form AP columns that encode homeodomain T.Fs

Some examples are:
-msh
- ind
- vnd

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14
Q

Based on the information above, explain how the integration of patterning information in 2 dimensions leads to neuroblasts getting their unique identity from their location

A
  • Columnar genes give neuroblasts their DV location
  • Segmentation genes give them their AP location
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15
Q

What is the ‘Isthmic organiser’ in terms of vertebrate anterior neural tube formation?

A
  • It forms at the boundary of the midbrain and hindbrain.
  • It is the name of this area, it becomes a new signalling centre for LOCAL patterning
  • Secretes FGF8
  • FGF8 patterns identity of neural genesis
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16
Q

Which signalling areas aid the formation of the DV axis / neural tube in vertebrates?

A
  • Signalling from the mesoderm is important for neural induction
  • The notochord (underneath the neural tube) is important for patterning of the neural tube and midline localisation
17
Q

Outline the role of Shh in vertebrates in terms of basic transduction mechanism

How are Shh (vertebrates) and HH (drosophila) differentin terms of where they are transduced?

A
  • Binds patched receptor
  • Removes patched inhibition of smoothened
  • smoothened then activates GLI (T.F.)
  • Shh is transduced in the cells cilium in vertebrates where as HH is in the cytosol
18
Q

How are the roof plate and floor plate of the neural tube induced?

And what happens once they have been induced in terms of signalling?

A

Roof plate:
- Lateral BMP signal in vertebrates (DPP in drosophila)

Floor plate:
- Shh signal from the notochord

Once they have been induced, the roof plate becomes the SOURCE of BMP and the floor plate becomes the SOURCE of SHH WITHIN the neural tube

19
Q

SHH from the floor plate is a morphogen for a)_________ neural fates, BMP from the roof plate is a morphogen for b)________ neural fates

A

a) Ventral
b) Dorsal

20
Q

SHH regulates expression domains of T.Fs, meaning that different concentrations of SHH either activate or repress a certain gene.

Genes in Class I: In order of repressed from Lowest conc of SHH required at the top to most
- Pax7
- Dbx1
- Dbx2
- Irx3
- Pax6

Class II Genes:
- Nkx6.1
- Nkx2.2 (vnd in drosophila)

What is the difference between class I and class II?

And what is the outcome of these expression domains?

A
  • Class I are normally ON but are repressed by different concentrations of SHH
  • Class II are normally OFF but are activated by different concentrations of SHH

The outcome is that the combination of genes expressed in each domain is a homeodomain code for the progenitor domain

21
Q

Use motor neurons to give an example of how AP and DV signals are integrated in the vertebrate nervous system

A
  • Motor neurons are formed ventrally along the whole neural tube (Nkx genes)
  • They also have different identities along the AP axis (Hox genes)
22
Q

In drosophila, ectodermal cells act as the neural progenitors.

What are the qualities of neural progenitors in general?

What 2 cell types can they turn into if they commit to a neural fate?

A

Proliferative and multipotent

Sense organ precursor
Neuroblast

23
Q

Refresh: What are the specific
a) segmentation genes
b) columnar genes
That give AP and DV location (respectively) to drosophila neuroblasts?

A

a) gsb genes
b) vnd genes

24
Q

Patterning genes regulate neurogenesis through the activation of pro-neural genes.

What are pro-neural genes?

A

Genes that plays a crucial role in the development of the nervous system, specifically the formation of neural progenitor cells and the subsequent differentiation of these cells into neurons

Regulation of pro-neural genes is what regulates neurogenesis

25
Q

What are the phenotypes of pro-neural gene mutants?

And what about the Scute mutant specifically?

A
  • Can be lethal if in the CNS
  • General patterning is ok
  • Subsets of neurons are missing
  • All due to a LACK of commitment
  • Pro-neural genes are required for commitment of progenitors to a neural fate

Scute:
- Lacks sensory bristles because SOPs did not form during development

26
Q

What are the qualities and some examples (in DROSOPHILA) of the transcription factors that are related to pro-neural genes?

A
  • Basic helix-loop-helix domain for DNA binding
  • They activate genes required for neural differentiation

Examples in Drosophila:
- Scute
- Atonal
- Amos
- Achaete

27
Q

Pro-neural genes in the drosophila are expressed in patches of ectodermal cells known as pro-neural clusters.

What is the point/outcome/mechanism of this?

A
  • Only cells in this cluster are COMPETENT to commit to neurogenesis
  • Once one cell has committed, it laterally inhibits its neighbours to produce a single SOP
  • Allows for even spacing of SOs
28
Q

What is the mechanism of lateral inhibition involving Delta-Notch signalling in the regulation of neural commitment?

A
  • The central cell expresses Delta strongly
  • Delta binds to Notch receptor (present on every cell)
  • This causes proteolytic cleavage of the Notch receptor, freeing the intracellular element
  • HES (anti-neural T.F) is upregulated in neighbouring cells, shutting down the expression of pro-neural genes
  • Therefore, neural fate inhibited in receiving cells and they take on epidermal fate
29
Q

Luckily for you mate, all pro-neural genes in Drosophila have homologues in humans

What are the homologues of the following genes in mice?

  • Atonal
  • Delta

and what happens in mutants of these genes?

A
  • Atoh1: Pro-neural gene
    Mutation = Cells fail to commit to hair cell fate
  • Jagged1: Notch ligand
    Mutation = Loss of lateral inhibition
30
Q

What are neural progenitor cells called in vertebrates? and where are they found?

(in the spinal cord, not the brain)

A

Radial glia cells, found in the Ventricular Zone (VZ)

31
Q

How is neurogenesis controlled in the vertebrate CNS?

A
  • Pro-neural genes and anti-neural HES genes are co-expressed in the ventricular zone radial glia cells
  • This mutual inhibition prevents the cells from committing but maintains their competent state
32
Q

Pro-neural mutants results in fewer neurons being produced, as expected, but Notch mutants ALSO result in fewer neurons. Why is this?

A
  • Because in Notch mutants, progenitors commit too early, ‘uses’ all the multipotent cells up, leaving none for later neurogenesis
33
Q

Continuous neurogenesis is due to a balance between mitogen activity that promote cell cycle progression and pro-neural factors that promote cell cycle exit!

Tumours are examples of abnormal proliferation and differentiation.

What is the mechanism behind

a) Astrocytoma
b) Medulloblastoma

A

a)
- HES highly expressed
- Strong Notch signalling maintains cancer as it prevents differentiation

b)
- Some caused by mutations that create uncontrolled SHH signalling, causing hyperproliferation of progenitors and inhibiting their differentiation

34
Q

Understanding asymmetric cell division: Drosophila SOs

The 4 cells of each mini sense organ (shaft, socket, sensory neuron and glial sheath) come from division of a single SOP

Each SOP divides asymmetrically to produce plla and pllb. These cells go on to divide asymmetrically again to form each cell type.

What mediates this?

A

Numb

Numb ensures asymmetric cell division and so numb mutants have defects in sense organ identity

35
Q

What does Numb do?

A
  • Numb is a general binary switch between two preprogramed fates (‘A’ or ‘B’)
  • It is NOT a specific cell fate determinant
36
Q

What is so great about asymmetric cell division?

A
  • In both the drosophila and the vertebrate, it helps maintain the number of progenitors while producing neurons!

(in vertebrates it is more complicated)

37
Q

Numb is required in the vertebrate CNS, however, more proteins are involved
It is involved in the apical complex. What is this and what does it do?

A

Apical complex = PAR + numb inactive
- When numb is inactive, Notch blocks proneural fate (progenitor maintenance)
- When numb is active, proneural genes result in neural fate

38
Q

Radial glia can do things a bit differently though, allowing for temporal flexibility in the mammalian CNS.

What can they do?

A
  • Symmetric Proliferative: Produce only 2 progenitors
  • Asymmetric Generative: As discussed
  • Symmetric Generative: Produce 2 neurons

The type of proliferation can change over time. this is maintained by the apical complex!

39
Q
A

Mechanisms of Brain Development (9 decks)

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