Development of the Neural Crest Flashcards
Levels of BMP regulate nervous system formation from the
Ectoderm
BMP near the midline is suppressed by
Noggin, Chordin, and FGF
Low levels of BMP allow the development of the
Nervous System
The first step of neural crest formation is to become distinct from both the
Adjacent ectoderm and neural tissue
The second step of neural crest formation is to begin
Migration
The third step of neural crest formation is to
Localize and differentiate
We can use quail-chick cell transplantation to create a chimeric embryo that allows us to
Map Neural Crest (NC)
The neural crest arises from the
Ectoderm
The qual-chick experiment allowed us to identify classic derivatives of the neural crest. What are the three cranial derivatives?
- ) Neurons and glia of cranial ganglia
- ) Cartilage and bone
- ) Connective tissue
The qual-chick experiment allowed us to identify classic derivatives of the neural crest. What are the three trunk derivatives?
- ) Pigment cells
- ) Sensory Neurons and glia
- ) Sympatho-adrenal cells
What are the levels of BMP for the following tissues?
- ) Epidermal
- ) Neural crest
- ) Neural
- ) High
- ) Intermediate
- ) Low
Forms at the boundary where presumptive neural plate meets the ectoderm
Neural crest
At this boundary, intermediate levels of BMPs in conjunction with FGF and other molecules induce
“snail” and “border specifier” genes
The “snail” and “border specifier” genes, in conjunction with BMPs and Wnts, then induce additional transcription factors that specify the
Neural crest
Stimulates c-Kit (pigment cells) and c-Ret (enteric neural precursors) expression on NC cells that have long migratory pathways
NC specifier transcription factor Sox10
In the initiation and pathways of trunk neural crest migration, first NC must change from epithelium to
Mesenchyme
To change from epithelium to mesenchyme, the NC loses its
6B class of Cadherins
The NC then migrates into a space filled with
Hyaluronic acid
Some disease conditions have deficiencies in several migratory cell populations such as
Pigment cells, hemopoetic cells, and germ cells
Specific ligand-receptor systems are used in
Neural crest migration
Different mutations in different strains of mice (called Dominant spotting and Steel) alter pigmentation and also lead to
Anemia and Sterility
These mutations encode either a specific receptor on the cell surface of the migratory cells or the ligand for that receptor that is produced by the cells in the
Migratory environment
Thus, for germ cells, hemopoetic cells, and NC-derived pigment cells, the tyrosine kinase C-kit receptor (mutated in dominant spotting mutation) on migratory cells binds
Steel factor ligan
Produced in migratory pathways used by germ cells, hemopoetic cells, and NC-derived pigment cells
Steel factor ligand
Production of ligand in the migratory pathway suggests that Steel peptide functions as a chemoattractant for
Receptor Expressing Cells
As in mouse, humans heterozygous for c-Kit mutation have
-as well as some deficits in hemopoetic and germ cell migration
Pigment migratory deficits
Provides progenitors for enteric nervous system
Migration of neural crest into the gut
The major congenital abnormality of the gut
-characterized by megacolon
Hirschsprung’s Disease
Individuals with Hirschprung’s disease have a deficiency of enteric ganglia and as a result suffer from
Constipation
Two non-linked mouse genes producing megacolon when mutated were also identified and turned out to represent another ligand-receptor pair. What is the:
- ) Receptor
- ) Ligand
- ) c-Ret
2. ) GDNF
c-Ret is expressed in
Neural crest cells
GDNF is expressed in the
Gut
In both c-Ret and GDNF mutant mice, NC migration is
markedly reduced and NC cells never reach the
Posterior gut
The mutation that causes the distal enteric ganglia not to form and results in Hirschsprung’s disease is a mutation in
c-Ret
Functions as a chemo-attractant as neural crest cells colonize the gut
GDNF
Neural crest cells interact with multiple cells/matrix components during
Migration
Characterized by deficits seen in the pharyngeal arches and pouches (pharynx, larynx) and also in neural crest derivatives (thymus, parathyroid, etc)
DiGeorge Syndrome
Develops as the neural crest enters the structure
Pharyngeal system
May be the result of initial failure of the pharynx and/or secondary failure of the neural crest
DiGeorge Syndrome
Variable size deletions 1.5-3 MB of human Ch22, which contains over 30 genes, are present in >90% of
DiGeorge patients
DiGeorge syndrome is the most common microdeletion in humans with an occurance of
1/4000
The region corresponding to the human DiGeorge region, 22q11, was found on mouse chromosome
16
Experimentation on mice showed that naturally occuring deltions indicated positive expression of
DiGeorge Syndrome
The relevant regions that lead to DiGeorge Syndrome include a gene for the transcription factor
Tbx-1 (A T-Box TF)
Developmentally important family of transcription factors
-Several mutations in this family are associated with human congenital abnormalities
T-Box gene family
Expressed in all cell types of the pharynx at mid-gestation, but NOT in the migrating neural crest cells
Tbx1
If Tbx1 is involved in Digeorge syndrome, this expression pattern suggests that deficiencies in NC-derived structures are likely secondary to failure of
Pharyngeal cells
When we knock out the Tbx-1 gene in mice, the mutant mice have multiple features of
DiGeorge Syndrome (i.e. cleft palate, low set ears, abnormal aortic arches)
Upstream regulators of Tbx-1 include
Sonic Hedgehog (Shh)
Bind to 5’ regulatory regions in FGF family genes
Tbx-1
If FGF is diminished in Tbx1 expression domain, phenotype similar to
Tbx-1 mutant mice
Is Tbx1 the only gene involved in DiGeorge syndrome?
No
An adaptor protein implicated in TGF-β and FGF signaling
-another contributer to DiGeorge syndrome
Crkl gene
In contrast to Tbx-1, Crkl is expressed in
Neural crest
Absence of Crkl (via gene KO) impairs
TGF/FGF signaling
The impaired signaling caused by KO of Crkl leads to severe defects in cardio vascular patterning that are specific to the
Neural crest (pharyngeal derivatives = normal)
Implicated in the initial formation of pharyngeal arches and pouches prior to neural crest migration
Tbx-1
Teratogenic influence on anterior nervous system and neural crest development due to alcohol intake
Fetal Alcohol Syndrome
The third leading cause of mental retardation behind fragile X syndrome and Down Syndrome
Fetal Alcohol Syndrome
2-3 oz hard liquor/day and or a single binge drinking
episode during pregnancy can induce
Fetal Alcohol Syndrome
What is the incidence of Fetal Alcohol Syndrome?
1/500 - 1/750 children
Giving prenatal mice alcohol showed that 12 hours after a single EtOH exposure, there was cell death in the
Anterior neural ridge
The mice were then exposed to alcohol at a stage when neural folds were forming and neural crest cells started to migrate. The result was that
NC migration was deficient (Much apoptosis)
The alcohol exposure also led to a reduced contribution to
Nasal and maxillary processes
Forms and disperses as a result of activation of a sequential cascade of transcription factor activation initially elicited primarily by specific levels of BMP
Neural Crest
Migration of neural crest cells to different destinations
is controlled in large part by
Specific ligand receptor systems
The ligand in the specific ligand-receptor systems functions as a
Chemoattractant
