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Development and Disease > Neurulation > Flashcards

Neurulation Flashcards

1
Q

What will the neural tube give rise to?

A 
The neural tube will give rise to:
•	the brain
•	the spinal cord
•	the cranial and spinal nerves
•	the eyes and other sensory organs
•	the neural crest
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2
Q

When does neurulation occur?

A

Neurulation occurs very early on in embryonic development. In humans, between weeks 3 and 4.

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3
Q

What steps make up neurulation?

A

Specification of the neuroectoderm

Neural plate formation

Neural plate folding

Neural tube closure

Neural crest migration

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4
Q

What is the CNS derived from and when is it specified?

A

The CNS is a derivative of the ectoderm, and becomes specified shortly after gastrulation.

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5
Q

How does the organiser form in a developing embryo?

A
  • Maternal signals deposited by the mother lead to the stabilization of nuclear b-catenin in the future dorsal region. They are initially confined to the vegetal pole which are then translocated towards one side of the dorsal side of the embryo.
  • b-catenin activates genes required for organizer function
  • The organizer becomes a source of signals that establish the axes of the developing embryo (amongst them Nodal, chordin, noggin)
  • These signals are also essential for neuroectoderm specification
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6
Q

What needs to be established to form the AP axis?

A

• In order to establish the anterior-posterior axis the distal visceral endoderm (DVE) needs to be established.

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7
Q

What happens once the DVE is specified?

A

This is located at the distal end of the embryo. Once it is specified its starts to express Lefty1.
• The cells that form the DVE will migrate proximally, as they migrate they recruit other cells that also start expressing Lefty1 and also start expressing DKK1.
• They will continue to migrate to the most proximal pole of one side of the embryo, which will form the anterior visceral endoderm.
• Lefty1 will antagonise Nodal (molecule of the Tgbf family) and DKK1 will antagonise Wnt.
• So the anterior visceral endoderm will supress the activity of Wnt and Nodal in surrounding tissues, so Wnt and Nodal will become confined to the opposite pole of the developing embryo
• Wnt and Nodal will induce the formation of the primitive streak
• Bmp4 is essential for the specification of the visceral distal endoderm and also coordinates with Wnt and Nodal to form the primitive streak. Bmp4 activity also induces Lefty 1 and Bmp4 re presses it (as seen in diagram).

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8
Q

What is the first reliable landmark of the anterior pole of the body?

A

The AVE is the first reliable landmark of the anterior pole of the body

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9
Q

How is neural tissue and epidermal cells specified from the ectoderm?

A
  • We have now established the anterior posterior axis in the embryo
  • Here we can see the dorsal region of the xenopus embryo.
  • The organiser highlighted in red is source of Chordin, Noggin and Follistatin. These molecules are all secreted antagonists of BMP4.
  • BMP4 is expressed in the ectoderm of the whole developing embryo
  • BMP4 normally induces the formation of the epidermis in the ectoderm, however around the organiser BMP4 activity is repressed leading to the formation of neural fate in the region next to the organiser
  • Therefore: Neural induction requires BMP antagonism
  • This process is conserved from flies to mammals, so needed in every organism
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10
Q

In mice what is the organiser that inhibits BMP antagonism?

A

The antagonists are released by a structure highlighted in red at the top end of the primitive streak that is called the gastral organiser which will inhibit BMP4 activity

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11
Q

How does the neural ectoderm form in humans?

A
  • As the primitive structure regresses a structure called the notochord will form underneath the neural ectoderm
  • The notochordal process is source of neural inducers (BMP antagonists such as chordin and noggin)

Once the neuroectoderm is specified, it narrows and elongates to subsequently fold and give rise to the neural tube. Start by watching this short preview of neurulation:

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12
Q

Give a brief outline how the neural tube forms?

A

• As the primitive structure regresses a structure called the notochord will form underneath the neural ectoderm
• The notochordal process is source of neural inducers (BMP antagonists such as chordin and noggin)
Once the neuroectoderm is specified, it narrows and elongates to subsequently fold and give rise to the neural tube. Start by watching this short preview of neurulation:

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13
Q

How does the mouse close its cranial and caudal neuropores?

A

Mouse
• Closure starts in 3 different places.
• Closure 1 (located between the hindbrain and the spinal cord) triggers the closing of the neural tube. This will extend anterior and posteriorly by the zippering process.
• Closure 2 (located between the forebrain and midbrain) will progress anterior and posteriorly. It will cause closure at the anterior portion of the hindbrain
• Closure 3 starts at the rostral part of the neural plate

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14
Q

How do humans close the neuropores?

A

Humans
• In addition to closure points 1, 2 and 3 there is closure points 4 (hindbrain) and 5 (caudal region of the neural plate which progresses anteriorly)
These are both examples of primary neurulation

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15
Q

What are the two modes of neural tube close?

A

• Primary neurulation:
o rolling-up of tube
o closure is by fold apposition then “zipping-up”
o Finally, at cranial and caudal neuropores
• Secondary neurulation:
o This happens at the most caudal end of the CNS (tail bud). Mesenchymal and mesodermal cells will become condensed to form a rod which will later on become hollow and form a tube.

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16
Q

What is Spina bifida?

A

• Spina bifida is defective closure of neural tube at border of 1º & 2º neurulation
o Somites 30-31 in human (2nd sacral) is where secondary and primary neurulation tubes fuse

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17
Q

Compare primary to secondary neurulation

A

This schematic aims to compare primary and secondary neural tube closure.

Primary neurulation involves elevation of the edges of the neural plate and come together and fuse which then detach

In secondary neurulation, the mesenchymal cells condense to form a solid rod. The lumen will then form in the rod which will then form the neural tube

Epithelialisation

18
Q

Describe the process of primary neurulation in detail

A
  1. The neural plate needs to be shaped. The whole embryo is elongating along the anterior-posterior axis and narrowing along the medial-lateral axis.
  2. The neural plate starts to fold along the Median hinge point (MHP) and will run along the midline of the neural plate along the AP axis
  3. The neural plate will sink underneath the ectoderm, brining the edges of the neural plate closer together.
  4. The edges of the neural plate will come closer together and will converge. Further hinge points are formed in the dorsal lateral wall.
  5. The edges will then fuse
  6. The neural crest will also migrate out of the domain and migrate away. They will form a huge variety of cell types.
19
Q

What is the process of convergence-extension

A

A process of lengthening by narrowing, which requires cells to become polarized, in the plane of the cell layer

shaping of the neural plate

20
Q

Describe the process of convergence-extension

What is this mechanism controlled by?

A
  • Cells will acquire polarity in the plane of the epithelium which will allow them to intercalate between each other.
  • This leads to the tissue becoming narrower and also increasing in length
  • The neural plate will narrow along the medial-lateral axis and extends along the anterior-posterior axis
  • The neural plate undergoes this transformation during the early stages of neurulation but the whole embryo is undergoing convergence and extension. The underlying mesoderm underneath the neural plate is also undergoing convergence and extension
  • This mechanism is controlled by the Planar Cell Polarity pathway
21
Q

What pathway regulates the process of convergence-extension?

Where in the pathway can you have mutations?

What is craniorachischisis?

A

• Wnt will interact with frizzled also working with co-receptors
• This leads to the activation of dvl 1,2 and 3.
• This activates a number of downstream effects in the cells which can entail transcription and cytoskeletal regulation (cell movement, shape and behaviours)
Mouse mutants in components of the Wnt-PCP pathway show neural tube defects:
• celsr1-/- (crash)
• vangl-/- (loop-tail)
• scribble-/- (circletail)
• dvl1/2
• fzd3/6
The neural plate is abnormally broad with a non-bending region between neural folds - leading to craniorachischisis (the neural tube is fully exposed to the extra embryonic medium)

22
Q

What does human mutations in the PCP pathway cause?

A

Human mutations in PCP genes are associated with craniorachischisis and other NTD

23
Q

Describe what cell wedging is and apical constriction

What is this pathway driven by?

A
  • The shapes around the MHP are changing there shape from a columnar shape to a bottle shape organisation
  • This forms a hinge and fold against each other
  • This process of cell shape change is driven by the cortical cytoskeleton in the apical portion of the cells
  • The cells along the apical side constrict forming a change of shape
  • This change of shape has to happen along the medial-lateral axis but should not constrict along the anterior-posterior axis otherwise it will form a ball instead of a tube

This constriction is driven by the Wnt signalling pathway
• The pathway controls the polarisation of the actomyosin at the apical cortex of the cells which drives constriction along the medial lateral axis.

24
Q

What is the position of the hinge points determined by?

A

The position of the hinge points is controlled by the Shh and Bmp pathways

  • Shh is released by the notochord that is found underneath the neural plate along the midline of the embryo
  • Shh influences the neural plate along the midline of the embryo and leads to the establishment of the medial hinge
  • Shh can also repress the formation of the dorsal lateral hinge points
  • MHP bending stimulated by notochord (Shh)
  • DLHP formation inhibited by Shh
  • Embryos without a notochord have DLHPs along whole body axis
  • BMP2 secreted from dorsal surface ectoderm also inhibits DLHP formation
  • Noggin (BMP antagonist), secreted from the tips of the neural folds, overcomes BMP2-mediated inhibition and enables DLHP formation
  • Shh blocks DLHP formation via inhibition of Noggin
  • In the upper spine, Shh is secreted strongly from the notochord and suppresses Noggin-mediated DLHP formation
  • In the low spine, notochordal Shh greatly diminished, Noggin is de-repressed, and DLHP formation occurs.
25
Q

When does neural crest migration occur?

A

Neural crest cell migration occurs prior to closure in the cranial NT, but after closure in the spinal region

  • Neural crest cells migrate away from the folding neural tube and will spread through the embryo to give rise to a diverse cell types
  • This process of neural crest cell migration occurs prior to closure in the anterior portions of the neural tube but after closure in the spinal regions
  • Migration away of neural crest cells in the anterior portion is important in accurate closure of the neural tube
26
Q

What other mechanisms are involved in neurulation?

A

Other mechanisms contributing to neural tube closure
• The dorsal ectoderm of the neural plate is generating forces that contribute towards the closure of the neural tube. It pushes towards the midline and helps with folding
• Programme cell death is also needed for fusion of the neural tube in the anterior portions.

27
Q

What does closure of the neural tube establish and what happens following fusion?

A
  • As the neural tube closes AP and DV axis are established

* The different structures of the CNS will become specified once the neural tube has formed

28
Q

Describe how Neural induction and AP patterning are tightly coordinated

A
  • Here we have a fish embryo prior to gastrulation
  • The organiser secretes molecules that are needed for neural ectoderm specification
  • As gastrulation progresses the embryo becomes more elongated and so does the neural ectoderm
  • The tissues surrounding the organiser (mesoderm) are taken away from the anterior portion of the embryo (neural ectoderm)
  • The mesoderm that is invaginating are a source of signals as well. They posteriorize the neural ectoderm: Fgfs, Retinoic acid and Wnts
29
Q

How is the the anterior neuroectoderm protected from posteriorizing signals?

A
  • Here we have a xenopus embryo at the end of gastrulation. The organiser is present on the dorsal region of the embryo.
  • The mesoderm has spread round in red underneath the ectoderm
  • The organiser creates a gradient of signals along the AP axis decreasing as it gets anterior.
  • Elongation of the axis takes the anterior portion of the neuroectoderm away from the source of posteriorizing signals
  • The anterior neuroectoderm is under the influence of molecular antagonists of the posteriorizing signals
30
Q

Development of the neural ectoderm will lead to the formation of these regions of the CNS along the AP axis (in a mouse embryo).

A

On image

31
Q

What do the primary vesicles give rise to?

A

The primary vesicles will become further subdivided into secondary vesicles as the pattern becomes refined. Each secondary vesicle will give rise to the different derivates in the CNS.

32
Q

What are primary and secondary signalling centres?

A 
The secondary signaling centers refine the initial pattern are more local effects in tissues that surround them:
•	ANB (anterior neural boundary): 
o	Fgf8, Wnt antagonists
•	ZLI (zona limitans intrathalamica): 
•	Shh
•	Roof plate: Wnts
•	MHB (midbrain-hindbrain boundary): 
•	Fgf8, Wnts
•	Morphogen gradients confer positional information around the signalling centres
33
Q

How are these secondary organisers established?

A

An initial rough pattern or regions are formed along the AP axis which will determine specific genes to be turned on which form these secondary organisers that determine cells into specific tissues

The first few secondary organizer’s to be established: ANB (anterior neural boundary) and MHB (mid-hindbrain boundary)

34
Q

What secondary organisers form first?

A

ANB and MHB

35
Q

What is the MHB?

What TFs form the MHB?

A

The mid-hindbrain boundary is between the hindbrain and the midbrain where signals are released that will give rise to form the tectum and cerebellum respectively.

The MHB boundary is prefigured in the gastrualting embyo caused by expression of transcription factors: otx2 (anterior portion of neural ectoderm covering forebrain and midbrain) and gbx1 (that is expressed in the future hindbrain)

36
Q

What causes the expression of Obx2 and Gbx1 in the midbrain and hindbrain?

A

Wnt is high in posterior parts and lower in anterior portion that leads to expression of the two genes.

On image

37
Q

What does the MHB secrete and how does this affect the midbrain and hindbrain?

A
  • Wnt and FGFs are secreted
  • The molecules generates gradients between the posterior and anterior axis
  • This influences tissues to form the midbrain and cerebellum
  • Give rise to different fates
  • The neural plates have different potential and ability to respond to these molecules, conferred by OTX and GBX.
38
Q

What are the 2 signalling centres for dorsal-ventral patterning of the neural tube?

How is this axis patterned?

A

Two signaling centers:
• Floor plate
• Roof plate

  • Shh released by the notochord induces the floor plate
  • The floor plate also releases Shh
  • A ventral to dorsal gradient of Shh activity patterns the ventral neural
  • tube

Summary
A combination of Shh, TGFb and Wnt signals pattern the neural tube
• A ventral to dorsal gradient of Shh activity patterns the ventral neural tube
• A dorsal to ventral gradient of Bmps patterns the dorsal neural tube
• A dorsal source of Wnt activity refines the levels of activation of the Hh signalling pathway

39
Q

What vitamins are associated with NTDs?

What disease are associated with NTDs?

A 
•	Maternal diet
o	Vitamin deficiency/malnutrition
	Folate
	Inositol 
o	High levels of sugar
•	Maternal obesity
•	Diabetes
•	Hypertermia
•	Teratogenic agents
o	Valproic acid (VPA)
A combination of these factors with genetic predisposition may lead to NTDs
40
Q

Is there a strong correlation between NTDs and folate acid?

A

Yes…

Strong evidence that folate acid supplementation reduces prevalence of NTDs

Clinical trials used women pregnancies that gave rise to NTDs and then gave them folate -> reduced NTDs

0.4-5.0mg/day

41
Q

Are there any adverse affects of folate acid?

A

• Probably no adverse effects
o Suggested problems: B12 deficiency (reduce detection by masking anaemia, allowing neurotoxic complications); promotion of colon polyps to cancer - both not confirmed
o Also reduces palate & heart defects

42
Q

What are folate resistant NTDs?

A

• But there are still NTDs that cannot be prevented by folate (“folate resistant NTD”)
• Inositol
o Can prevent NTDs in experimental models
o Current clinical trials, still insufficient evidence for a protective effect in humans

Development and Disease (19 decks)

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