Formation of the Neural tube and role of SHH

Question 1

Explain what is meant by induction in development

Answer 1

When one cell population or tissie acts on another tissue. The acting tissue is the inductor whilst the other is the responder, which will commit to a specific developmental pathway.

Question 2

One of the key signalling structures involved in formation of the neural tube is the ???????

Answer 2

Notochord

Question 3

Where is the notochord anatomically in relation to the neural tube?

Answer 3

Ventral

Question 4

What germ layer is the notochord derived?

Answer 4

Mesoderm

Question 5

Neural tube (think CNS) is derived from what germ layer?

Answer 5

Ectoderm

Question 6

The notochord is said to have what type of relationship to the neural tube?

Answer 6

Inductive

Question 7

Describe the phyiscal properties of the notochord, what does it go onto become?

Answer 7

Flexible rod like structure. Goes onto form the nucleus pulposus of the spinal cord.

Question 8

What are the key molecules that are produced by the notochord, and what is their function with regards to patterning of the neural tube?

Answer 8

• Noggin - acts by inhibiting BMP4
  
  • ​The absence of BMP causes patterning in the overlying ectoderm so it can turn into the neural tube
• Chordin - acts as a BMP4 antagonist

Chordin and Noggin are said to be negative regulators of development.

Question 9

Inhibition of BMP by noggin and chordin is a key step to the formation of the neural tube. When active, BMP4 ventralises ectoderm and mesoderm. If allowed to remain active, it would make ectoderm turn into epidermis and mesoderm into intermediate and lateral plate mesoderm.

If ectoderm is protected from exposure to BMPs, its default state is to become what type of tissue?

Answer 9

Neural

Question 10

After gastrulation has occured, the appearamce of the notochord and mesoderm induces the overlying ectoderm to thicken and form what precursor to the neural tube?

Answer 10

The neural plate

Question 11

What is the name given to the specialised ectoderm that makes up the neural plate?

Answer 11

Neuroectoderm

Question 12

After the neural plate structure is induced. the lateral edges of the plate start to undergo what changes to form the neural tube structure

The depressed midregion of the neural tube is known as what?

Answer 12

• The lateral parts of the neural plate become elevated
• The midregion becomes depressed to form the neural groove
• The folds move towards the midline and fuse together to form the neural tube
• The neural tube becomes separated from the overlying ectoderm, the overlying ectoderm repairs itself.

Question 13

At how many days does neuralation occur?

Answer 13

Days 19-22 (Week 3-Week4)

Question 14

Describe the changes that occur in cells of the neural fold in preparation for folding, and describe the two “hinge” points that are important for crucial to occur

Answer 14

• Cells take on a wedge-liked appearance
• two points on the neural tube are key for causing neural plate folding; the median hinge point and dorsolateral hinge point

Question 15

Fusion of neural tube begins in which region, and proceds in which direction?

Answer 15

Cervical

Proceeds in both a Cephalic AND caudal direction simulatenously

Question 16

After fusion of the neural tube has occured, what are the two holes called seen at the cephalic and caudal ends of the neural tube called?

Answer 16

Anterior neuropore

Posterior neuropore

Question 17

At what days should the anterior and posterior neuropore close?

Answer 17

Anterior closes at day 25

Posterior closes at day 27

Question 18

What “master regluator” of development is one of the key signalling molecules involved in differentiation of the neural tube?

Answer 18

Sonic hedgehog

Question 19

What structure releases SHH for patterning of the neural tube?

Answer 19

Notochord

Question 20

Sonic hedgehog produced by the notochord can act on the neural tube. As SHH has a relatively short range, it acts to produce what specialised portion of the neural tube? (note this is happening just as neural folding is also occuring)

What is the response of the floor plate as a result of the sonic hedgehog exposure

Answer 20

The floorplate

Floor plate makes it’s own SSH and results in the formation of motor neurones in the ventral part of the neural tube (DAVE)

Question 21

Aside from patterning of the neural tube, what other important processes is SHH important for?

Answer 21

• development of limb buds
• somite patterning
  
  • can causes cells in the ventral part of the somite, the scleratome, to undergo an epithelial t mesenchymal transition
  • This makes them become highly migratory and they can move wrds the signal source (in this case the notochord)
  • These cells will go onto form the vertebral column

Question 22

BMPs from the overlying ectoderm of the neural tube also have an important role in neural tube patterning - in particular the dorsal aspect of the neural tube. Explain how this occurs

Answer 22

• BMPs from the ectoderm upregulate PAX3 and PAX7 in order to form the roofplate
• These genes control the formation of sensory neurones in the dorsal aspect of the neural tube (DAVE)
• Therefore, we can say BMPS and SHH have a critical role in establishing the DV axis of the neural tube

Question 23

There are two factors that are crucial in the formation of the folding hinges of the neural tube. What are they, are at which points are they active?

Answer 23

• SHH - required for the median hinge point
• BMP2 - requied for the dorsolateral hinge point

Question 24

Although there are 2 potential types of hinge points, they are not always required for folding of the neural tube depending at the level (Upper/interediate/lower) of the spinal cord.

Where in the spinal cord (upper/intermediate/lower) would you expect to find these types of folds?

Answer 24

Upper spinal cord: Primarily Median hinge formation

Intermediate spinal cord: Both Median hinge points and dorsolateral hinge poins

Lower spinal cord: Primarily dorsolateral hinge points

Question 25

Formation of specific types of hinge points is strongly regulated by signalling molecules. Explain the signalling that occurs which leads to the formation of median hinge points and dorsolateral hinge points

Answer 25

**Upper Spine** SHH is strongly expressed, which is able to **inhibit noggin. As a result, levels of BMP2 remain high - thus MEDIAN HINGES are formed** **Lower spine** SHH is much less strongly expressed. As a result, noggin is free to **inhibit BMP 2, and dorsolateral hinges are formed.**

Question 26

The cause of **neural tube defects** such as **spina bifida**, where there is **improper closure of the neural tube isn't well understood.** One theory as to why this happens is the result of increased SHH expression within the neural plate. Bearing in mind the effects of SHH and BMP2 on the formation of different hinge types, suggest why increase in SHH could affect this process. **Also bear in mind that spina bifida most commonly occurs at the lower back.**

Answer 26

* SHH is under normal circumstances is required for the formation of **median hinges in the upper spine**, so you would expect extra SHH at this region to make any difference * **However,** under normal circumstances, SHH is usually at much lower levels, so if for whatever reason there was in an **increase in SHH levels at the lower spine, dorsolateral hinges would fail to form** **Remeber SHH inhibits noggin, leaving BMP2 to do it's thing and you get MEDIAN HINGES. If SHH isn't there, noggin stops BMP2 from doing it's thing and you get DORSOLATERAL HINGES.**

Question 27

SHH at a cellular level requires **two other genes that encode for transmembrane proteins.** Wht are these two proteins, and what family of transcription factors are activated?

Answer 27

Patched, smoothened Acts on the **Gli** transcription factors

Question 28

Describe signalling of SHH and how it controls patched, smoothened and Gli transcription factors

Answer 28

Question 29

SHH is **synthesized as an inactive precursor inside cells.** Which lipid is required for it's activation, and which transmembrane protein is required for it's delivery to outside the cell?

Answer 29

Cholesterol Patched

Question 30

Give examples of conditions that can arrise as a result of abberent SHH signallin

Answer 30