How has the study of the origins and development of the neural crest shed light on our understanding of development mechanisms and the origins of development disease?

Define neural crest as the ectodermal cells from the lateral neural plate. They go on to form various parts of the body such as:
Skull + teeth, PNS, calcitonin producing cells, parathyroid glands, carotid bodies, spiral septum, adrenal chromaffin cells.
They start from the neural tube but during development they migrate. Subsequently the study of these have given greater insight into cell migration mechanisms. Furthermore these neural crest cells are plastic and have allowed for improved understanding into how regulative development occurs.
Finally labelling experiments have allowed us to trace the lineage of differentiated cells to form fate maps. This has enabled us to understand the origins of many types of cells are actually neural crest and subsequenty help us to understand why conditions such as DiGeorge’s which causes craniofacial deformities can also cause      thyroid gland agenesis and persistent truncus arteriosus.

Neural crest fate mapping
Much of the knowledge on this was learnt from the early experiments of Nicole Le Douarin. She did experiments where she grafted the neural crest cells of a quail onto a chicken. (this allowed for identification due to differing heterochromatin patterns after staining). She then examined the fate of cells for different parts of the neural crest.
It showed that different parts of the neural crest adopted different fates:
Cranial - invade pharyngeal arches and around the brain. To form neurons, glia of sensory and parasympathetic cranial ganglia, dermis, menignes, teeth, bulk of the skull, melanocytes, thymus, parathyroids.

Vagal neural crest cells from the caudal hindbrain invade the gut and heart forming the ENS and aortico-pulmonary septum.

Trunk neural crest cells include all the neurons and glia of the sensory and sympathetic ganglia, adrenal medullary chromaffin cells, schwann cells and melanocytes.

Multipotency + regulative development
Subsequent to Nicole Le Douarin’s experiment, labelling of single cells were possible and this showed that even from the same region of neural crest, a single cell can form 2 different fates. For example a trunk vagal cell may form both the adrenal medullary chrommafin cells and also melanocytes. This showed that the neural crests were under regulative control
Furthermore in vitro and vivo experiments showed that a single neural crest cell can adopt different fates depending on its morphogen environment:
BMP4 which would be around the dorsal aorta causes sympathetic neuron fate
Neuregulin 1 type 3 instructs schwann cell fate
FGF2 instructs cartilage fate.
Furthermore transplant of trunk neural crest cells into vagal positions will result in the formation of a vagal phenotype.
Migration
Neural crest migration experiments helped elucidate a lot of info about migration.  It was found that ECM proteins such as fibronectin, laminin, tenascin and collagen all promoted migration and it was dependent on the NC cells having the corresponding integrins for them.
However to guide the cells there are repulsive factors such as sema3 and ephrinb which repel NC cells which express neuropillin and eph receptors. This was shown in Rodger Keynes experiment in which he proved that the reason why NC cells migrated through the caudal side of the somite was due to repulsive cues from the somite (shown as he surgically rotated the somites which resulted in the NC cells coming through the rostral side. To differentiate whether there were attractive or repulsive signals was shown with K.O experiments.
Long range attractive cues are also used and this is seen in the formation of the ENS whereby ret is expressed by the vagal neural crest cells that will form the enteric ganglia. They are attracted by GDNF from the gut cells. Mutation of c-Ret results in hirschprung’s disease.
Another area where migration and signalling patterns have been studied is in the pharyngeal pounces where the cranial neural crest cells migrate in distinct streams.
Consider the following barriers:
a1 there is an r3 level inhibitory signal (which in mice,chick and zfish is sema3).
ba2 at the r5 level is a physical barrier of the otic vesicle.
ba3 is another inhibitory signal which segregates the 3+4th arch in frogs and is Ephrin/Eph signalling.

We particularly see the importance of the physical barrier of the otic vesicle.
Diseases
The combination of the research of all the above mechanisms have allowed for the increase our knowledge on NC diseases.
As mentioned earlier hirschprung’s disease can occur due to c-ret mutation or mutation in the signalling moleucles such as BMP4 or neuregulin.
However the most common set of diseases are craniofacial malformations.
Cleft lip and cleft palate are failures of maxillary swellings to fuse but any of the 5 neural crest bulges can fail to fuse resulting in abnormal development.

This is linked with deletion of chromosome 22q11 which removes the Tbx1 gene. And causes Digeorge and Velocardiofacial syndrome, suggesting tbx1 is involved in craniofacial migration.
Originally written by Hilary Kosterlitz

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