Pintar - Neural Crest

Question 1

Inititation and pathways of trunk neural crest migration

Answer 1

The neural tube is essentially epithelial cells. We know that epithelial cells love to be near each other and have all of these adherence junctions to keep them together. Therefore in order for the neural crest cells to migrate they must lose the cadherins so they can become mesanchymal. They also need migratory space. They then migrate towards hyaluronic acid filled space.

Question 2

c-Kit and Steele

Answer 2

For germ cells, hematopoetic cells, and NC-derived pigment cells. You have the ligand, Steel, which acts as a chemoattractant and causes the receptor, C-kit, to follow. It is like placing a hot dog in front of a dog. Heterozygous mutation in c-Kit causes pigment migratory deficiency (pale spot on forehead).

Question 3

c-Ret and GDNF

Answer 3

Similar to steel and C-kit there is another ligand, GDNF, and a receptor, c-Ret. This group is responsible for neural crest migration through the gut. Mutation in c-Ret will cause peristalsis problems in the gut that lead to Hirschsprung’s Disease.

Question 4

DiGeorge Syndrome

Answer 4

• symptoms are: cardiac outflow and septal defects, thymus and parathyroid hypoplasia, cleft palate, small jaws, and low-set ears.
• There are variable size deletions between 1.5-3 MB on Ch22 that contain over 30 genes. They found a homologous region in mice.
• Tbx1 is potentially the gene responsible for DGS.
• CrkL is another gene near Tbx1 on chromosome 22 (22q11). It is an adaptor implicated in TGF-beta and FGF signaling. Mutation in this gene causes severe defects in cardio vascular patterning and septal defects. This is neural crest specific though and only affects structures that are derived from NC cells. This is different from TBX-1 in that Tbx-1 affects the phaynx
• It is an example where the interaction of the neural crest cells with the environment in which is migrates has an impact on development. The development of the pharynx area is not usually associated with the neural crest. Here we see multiple systems being affected, including neural crest derivatives and non-neural crest cell derivatives. Specifically the pharyngeal arch issues could be a mutation of secondary nueral crest signaling or initial pharynx itself. Turns out it is the Tbx gene

Question 5

Fetal Alcohol Syndrome (FAS)

Answer 5

• mental retardation, ,short openings between eyelids, low nose bridge, maxillary hypoplasia, smooth philtrum (ridge between nose and upper lip), and congenital heart disease.
• Causes apoptosis in neural crest cells. Causes a lot of cell death in rostral regions (head)

Question 6

sequential cascade of transcription factors for NC

Answer 6

1) NC forms boundary where presumptive neural plate meets endoderm
2) intermediate levels of BMP in conjunction with FGF and other molecules induce “snail” (transcription factor) and then other “border specificer” genes such as Sox10, which is a transcription factor gene that stimulates c-Kit and c-Ret at this boundary
3) These genes in conjunction with BMPs and Wnts then induce additional transcription factors that specify neural crest as well as additional genes in migration.
4) Sox10 acts as a transcription factor for c-kit and c-ret

Question 7

Noggin, Chordin, FGF

Answer 7

Inhibit BMP

Question 8

From the neural crest, which derivatives from the trunk and which the cranial things?

Answer 8

trunk - pigment cells, Sensory neurons, sympatho-adrenal cells
cranial - neurons and glia of cranial ganglia, cartilage and bone, connective tissue

Question 9

Tbx-1

Answer 9

Upstream target is Shh
One target of Tbx-1 is FGF family of genes
If FGF is diminished in Tbx-1 expression domain then we se the same DeGeorge phenotype