Developmental Disorder

Question 1

How is transcription factor expression controlled in the early embryo?

Answer 1

It is restricted due to hierarchical level.

Question 2

How is right and left variation determined?

Answer 2

It is all genetically controlled.

Question 3

What forms at the anterior end of the primitive streak?

Answer 3

The node

Question 4

What is the node?

Answer 4

Thickening of cells at the anterior end of the primitive streak which is a genetic determinant in body axis formation and a major signalling center in vertebrates.

Question 5

What are organisers?

Answer 5

They pattern the surrounding cells and tissues by secreting signalling molecules.

Node cells secrete nodal (& FGF): signalling through tyrosine kinases.

Question 6

What does nodal do?

Answer 6

Activates a receptor tyrosine kinase that signals to adjacent epiblast cells to form neural ectoderm which in turn forms the brain.

AVE restricts the primitive streak from moving anteriorly.

Nodal is a key factor for establishing the left side.

Question 7

Which cells form the nodes?

Answer 7

Anterior Visceral Endoderm (AVE)

Question 8

How is fluid flow directed to the left of the embryo body to establish body symmetry?

Answer 8

Midline ventral node cells have cilia that spin clockwise producing a leftward flow of fluid.

Question 9

How do we know that cilia are found in midline ventral node cells that carry fluid to the left of the primitive embryo?

Answer 9

A dynein mutant mouse will have randomized L-R organ location.

If force flow to the right then L-R axis is reversed.

Question 10

How does nodal end up on the left side of the primitive embryo?

Answer 10

Fluid flows right to left setting up cascade of nodal on the left of the embryo.

Ca++ release from left-side cells also increase nodal.

The initial small difference of nodal levels are amplified by a positive feedback loop: High nodal levels lead to activation of nodal gene thus resulting in more nodal.

High nodal on the left leads to expression of Pitx2 TF which (along with nodal) makes the heart form in left lateral mesoderm.

Question 11

What happens if Nodal and Pitx2 are symmetrically expressed?

Answer 11

Randomised organ location.

Question 12

What does lefty1 do?

Answer 12

Restricts movement of left side proteins in the left side of the body.

It is expressed on the left half of the notocord and forms a midline barrier.

It is a nodal antagonist which prevents nodal from crossing to the right.

Question 13

What does lefty2 do?

Answer 13

Mirrors left side expression of nodal

Question 14

What does snail do?

Answer 14

It is a transcription factor that determines right side expression. It is produced in response to lack of nodal

Question 15

What does pitx2 do?

Answer 15

Along with nodal: Makes the heart form in left lateral mesoderm.

It is an important protein for gut looping.

Question 16

What family of proteins is Lefty1 a part of?

Answer 16

TGFbeta family of growth factors.

Question 17

What happens at the node to stimulate nodal secretion? How is this different to the right side?

Answer 17

On the left side:

Sonic hedgehog (Shh) is produced in the node which stimulates caronte (cerberus)

Caronte inhibits BMP from inhibiting production of nodal thus resulting in nodal expression on the left side.

Nodal inhibits snail and stimulates Pitx2.

On the right side:

No Shh is produced which results in FGF8 production. FGF8 inhibits caronte (cerberus) which means BMP can carry out its function of inhibiting nodal production on the right side.

Lack of nodal means snail can be expressed and Pitx2 is inhibited.

Question 18

What causes left-right asymmetry?

Answer 18

Loss of left-side asymmetry possibly due to loss of dynein. (condition called situs inversus)

Loss of pitx2 is called rieger syndrome (changes in teeth development, facial development, etc)

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