19. Hedgehog & Wnt signalling Flashcards
what type of structure is a denticle
a bristle like structure
where are denticles present in drosophila
present on the anterior half - posterior half is smooth
who identified segment polarity mutants
Volhard & Wieschaus
describe segment polarity mutants in drosophila
a group of mutants that affected the patterning within segments of the drosophila body
what do hedgehog genes do
produces hedgehog proteins that are morphogens - signalling proteins involved in embryonic development
how many types of hedgehog proteins in drosophila
1
how many types of hedgehog proteins in vertebrates
3
name the hedgehog proteins found in vertebratea
sonic, indian, desert
what modifies hedgehog proteins
cleavage and addition of cholesterol
define morphogen
signalling proteins involved in embryonic development
what is the purpose of cholesterol in relation to hedgehog
embeds hedgehog in the in the cell membrane
what is the role of wingless
switch on expression of hedgehog in the adjacent stripe
how are drosophila embryo segments marked out
alternating expression of wingless (black) and hedgehog (red)
= red and black stripes
what is the boundary between the wingless and hedgehog stripes called
the parasegment boundary
what does hedgehog do in its segment
induces diffusible wingless in the adjacent cell
what happens if hedgehog lacks cholesterol
it is capable to diffuse - this means it can switch on wingless in more cells
describe the hedgehog receptor
patches
= 12 transmembrane domain
how does patched work
the KO of patched activates the hedgehog response - involved smoothened (Smo) protein
what happens in the absence of hedgehog (Hh)
patched receptors hide smoothened protein in vesicles
Ci/Cos2/Fu forms a complex on microtubules = Ci is phosphorylated by protein kinase A
Ci enters and inhibits transcription
what happens in the presence of hedgehog (Hh)
Hh binds to patched receptor
smoothened (Smo) moves to the plasma membrane
Smo interacts with Cos2/Fu = dissociates from microtubules
Cos2/Fu is phosphorylates
unphosphorylated Ci moves to the nucleus = binds CBP and activates target genes
what does the nervous system form from
ectoderm
- overlying the notochord
what secretes sonic hedgehog (Shh)
the notochord
what does Shh induce
the floor plate which secretes further Shh
at high concentrations of Shh, what is specified
motoneurons
what is specified at medium Shh conc
V2 interneurons
what is specified at low Shh conc
V1 interneurons
how can Hh signalling lead to cancer
name a specific cancer
Hh stimulates stem cell proliferation in the basal layer of skin
excess Hh leads to over proliferation
= basal cell carcinoma
name a tumour suppressor that acts against Hh
Ptc1
how does Ptc1 inhibit Hh
inhibits Hh signalling
who is particularly vulnerable to Basal cell carcinoma, why?
Gorlin’s syndrome
- they have mutated patched receptors
what could be a potential therapeutic avenue for treating some cancers
anti-cancer drugs based on molecules that inhibit Hh signalling
what are Wnt proteins involved in (2)
cell cycle regulation
immune cell maintenance
what is the name Wnt an amalgamation off
wingless (segment polarity gene)
Int (mouse gene)
how many types of Wnt in:
humans
drosophila
11-12
1
describe the structure of Wnt
many cysteines
what is the benefit of there being many cysteines in Wnt
allows them to form intra-chain disulphide bonds that increase stability
like Hh - Wnt is modified:
what modifies Wnt
how is it modified
modified by porcupine enzyme
fatty acid palmitoleate is added to the conserved serine
what are the two receptors for Wnt
LRP
frizzled
describe what happens in the absence of Wnt
LRP is not phosphorylated
cytoplasmic complex phosphorylates beta-catenin
beta-catenin is then targeted for proteosomal degradation
TCF represses transcriptional targets
describe what happens in the presence of Wnt
Wnt binds to LRP and frizles
LRPs cytoplasmic tail phosphorylates axin
beta catenin is released from the axin held complex
beta catenin translocates to the nucleus - binds to TCF = activating transcription of target genes
what is the role of wingless
to induce Hh expression in adjacent cells
what is an essential function of Wnt
establishing the nieuwkoop centre
what can be done to induce a second nieuwkoop centre to form
add beta-catenin mRNA to the ventral side = second centre and duplicated axis of development
what can over-expression of Wnt cause
cancer
how can Wnt’s cause cancer
loss of APCs = excess Wnt signalling
prevent beta-catenin degradation = prolonged over expression of genes
what mediates the destruction of beta-catenin
APCs
what does APC stand for
adenomatous polyposis coli
