What will the neural tube give rise to?
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
When does neurulation occur?
Neurulation occurs very early on in embryonic development. In humans, between weeks 3 and 4.
What steps make up neurulation?
Specification of the neuroectoderm
Neural plate formation
Neural plate folding
Neural tube closure
Neural crest migration
What is the CNS derived from and when is it specified?
The CNS is a derivative of the ectoderm, and becomes specified shortly after gastrulation.
How does the organiser form in a developing embryo?
- 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
What needs to be established to form the AP axis?
• In order to establish the anterior-posterior axis the distal visceral endoderm (DVE) needs to be established.
What happens once the DVE is specified?
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).
What is the first reliable landmark of the anterior pole of the body?
The AVE is the first reliable landmark of the anterior pole of the body
How is neural tissue and epidermal cells specified from the ectoderm?
- 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
In mice what is the organiser that inhibits BMP antagonism?
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
How does the neural ectoderm form in humans?
- 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:
Give a brief outline how the neural tube forms?
• 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:
How does the mouse close its cranial and caudal neuropores?
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
How do humans close the neuropores?
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
What are the two modes of neural tube close?
• 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.
What is Spina bifida?
• 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
Compare primary to secondary neurulation
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
Describe the process of primary neurulation in detail
- The neural plate needs to be shaped. The whole embryo is elongating along the anterior-posterior axis and narrowing along the medial-lateral axis.
- 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
- The neural plate will sink underneath the ectoderm, brining the edges of the neural plate closer together.
- The edges of the neural plate will come closer together and will converge. Further hinge points are formed in the dorsal lateral wall.
- The edges will then fuse
- The neural crest will also migrate out of the domain and migrate away. They will form a huge variety of cell types.
What is the process of convergence-extension
A process of lengthening by narrowing, which requires cells to become polarized, in the plane of the cell layer
shaping of the neural plate
Describe the process of convergence-extension
What is this mechanism controlled by?
- 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
What pathway regulates the process of convergence-extension?
Where in the pathway can you have mutations?
What is craniorachischisis?
• 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)
What does human mutations in the PCP pathway cause?
Human mutations in PCP genes are associated with craniorachischisis and other NTD
Describe what cell wedging is and apical constriction
What is this pathway driven by?
- 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.
What is the position of the hinge points determined by?
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.
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The concepts and language of development54
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Animal Models in Development19
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Methods in Development35
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Signalling Pathways42
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Primary Cilla, signalling and development21
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Genome editing and sophisticated transgenesis59
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Neurulation42
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Boundary Formation41
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Somitogenesis34
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Organoids and stem cells30
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Eye development39
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Ear development35
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Neural Crest Part 126
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Neural crest part 217
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Heart development46
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Heart Development Part 223
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Limb Development54
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Limb Development Part 210
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Cortical Development53
