Pintar - environmental effects on development

Question 1

FGF pathway

Answer 1

critically important for development of organs, bone cartilage.

• There is a transmembrane protein called “Heparan Sulfate” which is a proteoglycan and has sugar chain coming off of it. This allows for the FGF (ligand) to bound to the sugar chain and thus easily identifiable by the FGF receptors.
• involved in left-ride sidedness. Promotes continued chordin and noggin expression, which in turn inhibits BMP4. This promotes more mesoderm production.

Question 2

Nodal

Answer 2

if there is a mutation in the gene “nodal” the primitive streak will not be made. Therefore the mesoderm will not form. Generally BMP4 and Nodal are opposites. When Nodal is on there will be things that antagonize BMP4 and inhibit it.
Basically, Nodal is responsible for making the primitive node. It should not be expressed everywhere. Therefore BMG-4 is an antagonist that doesn’t allow nodal to be active. BMG-4 is made by AVE. Noggin and Cordin bind to BMG-4 in what will be the primitive node so that nodal can be active there and create the primitive node.

Question 3

TGF-beta signaling

Answer 3

1) TGF-beta ligands bind to the receptor as a dimer
2) This causes another receptor to come into close proximity to the original receptor as we see quite often with kinase receptors.
3) This causes the kinase to phosphorylate a folded Smad.
4) This will unfold the Smad and allow it to enter the nucleus and bind to the TGF-beta-response element in target gene.
- antagonists of TGF-beta peptides can regulate activity by binding TGF-beta receptors or also preventing them from dimerizing.

Question 4

Retinoic Acid/FGF and Hox

Answer 4

We can see patients with their legs stuck together. Why does this happen? Basically The Retinoic acid (RA) and FGF antagonize each other. They are in a constant tug of war that RA always wins. They start at the top of the body and work their way down. FGF is responsible for activating the HOX genes. Therefore if FGF is being silenced by RA too quickly then the posterior (feet) part of the body doesn’t form properly

Question 5

Trisomy 13

Trisomy 18

Answer 5

13 - midline defects, cleft lip, CNS malformations, microotphalmia, holoprosencephaly
18 - intrauterine growth restriction, clenched hands, low set ears, rocker bottom feet, prominent occipital lobe

Question 6

Thaliddomide

Answer 6

cases tiny arms and notmal sized hands

Question 7

Goosecoid

Answer 7

also expressed in the node. It is a transcription factor that will allow anterior structures to be induced in mesoderm moving anterior. Too much goosecoid will lead to two heads.

Question 8

What will too little noggin/chordin cause?

Answer 8

because noggin and chordin are responsible for binding BMP-4 and allowing Nodal to do its thing, if we have too little Noggin/Chordin, then BMP-4 will be overactive and Nodal will be less active. This causes posterior mesoderm to never form.

Question 9

Two major functions of FGF in mesoderm

Answer 9

1) induces/helps maintain a second region of nodal expression, which ultimately leads to left/right sidedness following activation of another signal cascade.
2) FGF promotes continued chording and noggin expression.

Question 10

Brachyury

Answer 10

Knockout of this gene will cause tail-less phenotype. It is responsible for forming the posterior mesoderm

Question 11

Pathway starting from RA

Answer 11

RA –> Has inhibitory affects on FGF
FGF–> Responsible for continually making Noggin and Chordin
Noggin/Chordin –> Inhibit BMP-4
BMP-4 –> inhibits Nodal

RA is made more anteriorly, FGF is made more posteriorly. RA slowly turns off FGF from head to toe. Too much RA or not enough FGF will cause posterior mesodermal mutations.
FGF exposure is also needed to turn on 5’ HOX genes.