Hedgehog signalling - part 2 Flashcards
(29 cards)
What phenotype is predominantly produced from a reduction in sonic hedgehog function?
Holoprosencephaly (HPE)
What happens to an individual with HPE?
They have incomplete development at the midline of the brain and face
Is the phenotype the same for all patients affected by HPE?
No, the severity and phenotype varies
Can be cyclopia or just a single incisor
What is the frequency of HPE in live births?
1:10,000 births
What is the frequency of HPE in miscarried foetuses?
1:250 miscarries
Describe the rare familial dominant form of HPE
Several loci
One includes shh
Mutations identified
What happens if you knockout the mouse sonic hedgehog gene?
The mouse has cyclopia
Where is environmental HPE an endemic?
In western USA during the 50’s in cattle and sheep
What was the environmental HPE endemic traced back to?
Corn lilly
Teratogens identified - steroidal alkaloids
What do corn lilly teratogens resemble?
Cholesterol
What do corn lilly teratogens induce in chick embryos and what phenotype does this produce?
Severe HPE (cyclopia) Arrest of midline development causing the failure of forebrain division and the absence of two telencephalon vesicles; and causes the optic field to not divide
What happens in a chick embryo without sonic hedgehog?
No midline forms and the eye field does not divide
Treating the chick embryo with cyclopamine phenocopies what?
The shh mutant
Where does cyclopamine block the induction of gene expression?
In the neural tube
Does cyclopamine interfere with cholesterol modification and how is this known?
No, sonic hedgehog processing in cultured cells is unaffected by cyclopamine
Does cyclopamine inhibit sonic hedgehog signalling and how is this known?
Yes, sonic hedgehog normally induces gene expression in explants of neural tube in vitro, but this induction is blocked when cyclopamine is added to the culture medium
What are isl1/2 and HNF-3?
Two genes that are switched on in response to sonic hedgehog signalling
What is the phenotype of a mouse knockout mutant of sonic hedgehog?
Cyclopia
What is the phenotype of a human heterozygous mutant of sonic hedgehog?
Variable effects:
Undivided brain, cyclopia, cleft palate, nasal defects, dentition
What do the phenotypes of human heterozygous mutants of sonic hedgehog suggest about the gene?
It acts during multiple stages of midline craniofacial development
This is confirmed through experimental manipulation by implanting alpha-shh secreting cells in chick embryos at different stages
What is the most common teratogenic birth defect?
Foetal alcohol syndrome
Describe the phenotype that an individual with foetal alcohol syndrome might show
Small head size Reduced philtrum Low nose bridge Brain can be much smaller Mental retardation HPE
Describe the variety of effects that a mouse model with foetal alcohol syndrome might show
Neural crest cell migration - premature differentiation into facial bones
Induces neuronal apoptosis in forebrain
Disrupts cell adhesion (L1)
Affects shh expression
Does ethanol affect sonic hedgehog?
Yes
