Hedgehog Signalling Flashcards
(23 cards)
What is Drosophila hedgehog?
Secreted protein that functions in many developmental process
How does hedgehog interact with Patched?
Hh binds to Ptc. Causes genes to be switched on.
Some encode other signalling molecules
How does hedgehog induce a secondary signal?
Binds to Ptc. Leads to release of Dpp.
Induced patter along A-P axis
How does Hh affect wing patterning?
Normally expressed in posterior.
Direct expression in anterior - leads to mirror image duplication of wing pattern along A-P axis
What happens if Shh homolog miss-expressed in chick limb bud?
Mirror-image duplication
Where does Shh act?
Primary regulator of cell types in neural tube
Induces feather buds
Kidney development, bone formation
How does Shh act in neural tube?
Made in notochord
Induces expression of Shh in floorplate cells - induces ventral motor neurones and antagonises ventral dorsal signals
What happens if the notochord is surgically inserted in the wrong place?
New set of neural axons develop at wrong place
What happens if you transplant the floorplate?
New set of neural axons develop at wrong place
What specifies ventral portion of neural tube?
Gradient of Shh
Decreases as you move dorsally
Induces / represses specific transcription factors
What causes HPE?
Corn lily teratogens that resemble cholesterol - cyclopamine
How does cyclopamine affect formation of midline?
Cyclomapine blocks induction of gene expression in neural tube. In presence of cyclomapine, no gene expression of floorplate cells induced by notochord
How is cholesterol linked to hedgehog?
N-terminus of hh is modified and cholesterol is added to make it active
How does cyclopamine inhibit shh signalling?
Induction of shh signalling is inhibited from Shh to neural tube
What are the most common birth defects of Foetal Alcohol Syndrome?
Small head size Reduce philtrum Low nose bridge Brain can be much smaller Mental retardation HPE
How does ethanol affect sonic hedgehog?
Reduces shh protein and increases apoptosis
Inhibition of shh activity in PME cells may affect specification of midline facial structures
How does hedgehog binding affect Smoothened activity?
Relieves inhibition of Smoothened activity
Hh binds to Ptc which activates Smo
What occurs without Patched?
Constitutive activation of targeted genes - as Ptc not
What occurs with Patched without Shh?
Patched moves cholesterol outside the cell
Smo taken into endosomes
How is Shh involved in cancer?
Shh has mitogenic activity (promotes mitosis) in a number of settings
How is pathway-specific cancer therapy used in Shh pathway?
Cyclopamine might be useful to supress hh pathway in tumours, but oncogenic forms of Smo are much more resistant
How can you overcome the more resistant Smo?
Chemically synthesise derivatives - add side groups to cyclopamine to create one which is much better at inhibiting Smo
What are the problems of Smo inhibitors as cancer treatments?
- Resistance - cancer cell has more mutations
2. Activation downstream of Smo - other oncogenic pathways can activate Gli
