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Developmental Biology > L5 - Hh and Wnt Signalling > Flashcards

L5 - Hh and Wnt Signalling Flashcards

1
Q

What are Hh and Wnt signalling involved in?

A

Patterning tissues
Development of organs
Regulation of stem cell fate/cell division
Maintenance and initiation of cancer

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2
Q

How was Hh discovered?

A

Discovered by Nüsslein-Volhard and Wieschaus - 1980
In Drosophila
Segment polarity gene

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3
Q

How was Wnt discovered?

A

Wg + int = Wnt

In mice

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4
Q

How do Hh and Wg interact in Drosophila embryos?

A

Hh acts in a reciprocal loop with Wg
During segmentation in flies – Hh and Wg maintain each other’s expression in an autoregulatory loop
- Genes are dependent on one another
- Loss of Wg = loss of Hh expression

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5
Q

What are the different types of Hh in multicellular animals?

A

Sonic Hedgehog, Desert Hedgehog, Indian hedgehog

No Hh in C.elegans

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6
Q

What are the different types of Wg in multicellular animals?

A

18 Wnts

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7
Q

Hh signalling method

A
  1. Hh translated with an N-terminal signal sequence - targets them to secretory pathway
  2. Signal sequence is removed and the protein undergoes autoproteolytic cleavage
    - Catalysed by the C-terminal of the protein
  3. C-terminus of N-terminal coupled to cholesterol
  4. N-terminus of N-terminal coupled to Palmitoyl group
    - Both cholesterol and palmitate are hydrophobic
    - Render Hh insoluble in water and target it to membranes
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8
Q

Palmitoyl and cholesterol are both?

A

Hydrophobic

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9
Q

Hh signalling - short range

A

Hydrophobicity of Hh would make it impossible for it to leave cell membrane
Only allow signalling to neighbouring cells

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10
Q

Hh signalling - long range

A

Action of Dispatched protein and Scube glycoproteins important
- Help load Hh molecules on lipoprotein particles
Cytonemes
In the ECM - heparan sulfate proteoglycans

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11
Q

Wt signalling method

A
  1. Produced with a signaling sequence that is cleaved off when it enters the secretory pathway
  2. Modified by palmitoylation – palmitoleic acid modification of ser209
    - Palmitate is hydrophobic
    - Hydrophobicity makes Wnt insoluble in water
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12
Q

Wt signalling - long range

A

Lipoprotein particles or cytonemes - present ligand to other cells
Wntless 7 pass transmembrane protein – helps Wnt get to membrane
In the ECM - heparan sulfate proteoglycans

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13
Q

What are cytonemes?

A

Long cellular protrusions

Wnt producing cell use them to touch other cells and signal to them to change their behavior

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14
Q

Hh signalling model

A

Signal transduction model

Proposed by Hooper and Scott - 2005

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15
Q

Hh signalling - Ptc gene

A

12 pass transmembrane protein
Can bind hedgehog
Acts in a negative way - continuously inhibits a positively acting component - Smo - when the ligand is absent

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16
Q

Hh signalling - Smo gene

A

7 pass transmembrane protein

Acts in a positive way

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17
Q

What sort of complex does Ptc and Smo form?

A

Not present in a stoichiometric complex

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18
Q

What was discovered about Ptc in Drosophila experiments?

A

Single Ptc molecule can inhibit a large number of Smo molecules

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19
Q

What does Ptc regulate?

A

Subcellular distribution and stability of Smo

Trafficking of Smo to a compartment where Smo gets degraded

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20
Q

What does Ptc do if no Hh is present?

A

Ptc stops Smo reaching cell surface

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21
Q

What does Ptc do if Hh is present?

A

Ptc binds to HH and they both get internalized and degraded

Smo gets trafficked to cell surface

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22
Q

What 3 changes does Smo go through?

A

Relocation
Accumulation
Phosphorylation

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23
Q

If no Hh in cilia?

A

Ptc1 is localised to the cilium of the cell and smo is excluded from this territory
Hh binding to Ptc is removed from cilium
Allows smo to accumulate and initiate signaling

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24
Q

What is Ci?

A

A transcription factor

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25
If no Hh which two complexes keep Ci out of the nucleus?
Costal2 (scaffold protein) and fused serine threonine kinase | Ci and suppressor of fused gene (gene without clear domains)
26
What conditions have to be met for 3 other kinases to act on Ci?
The complex costal2 and fused serine threonine kinase has to be bound to Smo
27
What are the 3 kinases that act on Ci?
Casein kinase I Protein kinase A Glycogen synthase kinase 3 beta
28
The long form transcription factor Ci is?
A transcriptional activator It is processed under the influence of the 3 kinases to a shorter form This happens via Slimb and involves ubiquitination
29
The short form transcription factor CiR is?
A transcriptional repressor | Hh target genes that are actively repressed
30
What happens to the interaction of Ci with the 3 kinases when a ligand is present?
When there is ligand present, the interaction of Ci with the three kinases is blocked A full length Ci is released – actively promotes transcription of target genes
31
How does Hh signalling act on its own pathway in a negative way?
Induction of Ptc | Reduced level of Hh activation
32
How does Hh signalling act on its own pathway in a positive way?
Induction of Gli1 | Gli cannot be proteolyzed into a repressor
33
What is the role of Hh in Drosophila wing patterning?
In drosophila wing imaginal disk Hh is expressed in posterior compartment It diffuses into anterior compartment where it induces expression of decapentaplegic This helps to pattern the wing
34
What is the role of Hh in vertebrate neural development?
Neural tube cells differentiate into different neurons depending on how long and how much Shh Sources of Hh protein - Notochord - Floor plate
35
What is the role of Hh is AP patterning of the limb bud?
Hh is active is in the posterior limb bud where it forms the zone of polarizing activity A region that can confer posterior identity to and outgrowth of the forming limb
36
Loss of Hh signalling diseases
Holoprosencephaly – loss of ventral brain structures so eyes fuse Cyclopamine - can inhibit Smo and block the Hh signal Polydactyly – extra digits (misregulation) Syndactyly (misregulation)
37
Gain of Hh signalling diseases
Basal cell carcinoma Medulloblastoma Rhabdomyosarcoma Inactivation of Ptc1 or Sufu - tumor suppressor genes Activating mutations of Smo - Smo is a protooncogene
38
Genetic diseases related to Hh
Gorlin syndrome Large numbers of BCCs Due to heterozygosity for Ptc1 (defective patch)
39
Cancer treatment by Smo inhibitors
GDC-0449 - treated patients Initially good result But tumor cells acquire resistance by a mutation in Smo
40
Wnt signalling method
1. Beta catenin is continually produced and is bound by destruction complex 2. Beta catenin is phosphorylated by Gsk3 beta and CK1a 3. Phosphorylated beta catenin is recognised by Slimb/BetaTrcp and ubiquitinated 4. Ubiquitinated beta catenin is destroyed by the proteasome - freeing destruction complex 5. Wnt binds to its receptors frizzled and arrow/lrp5/6 and brings them together - initiates signal 6. Dishevelled is recruited to the Fz receptor and phosphorylated 7. Leads to recruitment of the destruction complex - Dsh binding axin, phosphorylation of arrow/lrp5/6 by gsk3b creating binding sites for axin - Slimb is lost from complex 8. As a result Beta catenin that is produced will still bind the complex and become phosphorylated 9. But is will not be ubiquitinated - remain bound to destruction complex 10. The system clogs and newly produced beta catenin will start accumulating 11. Beta catenin enters nucleus to displace groucho to start activating transcription
41
What is the role of Wnt signalling in Drosophila?
Expressed at D/V boundary of wing | Required for patterning and outgrowth
42
What is the role of Wnt signalling in C.elegans?
Regulation of neuronal fate leading to migration of two neuroblasts QRd and QLd
43
What does the small intestine consist of?
Crypts and villi
44
What cells occupy the villi?
Differentiated enterocytes, enteroendocrine cells and goblet cells
45
What cells occupy bottom of the crypt?
Paneth cell
46
What cells occupy higher positions?
Stem cell
47
Where is Wnt expressed in crypts and villi?
Wnts are expressed by the stroma below the intestinal crypts
48
What happens if you block Wnt signalling in the intestine?
If you block Wnt signaling it will cause loss of stem cells in the colon crypt Wnt signalling is required for maintenance of the stem cell compartment
49
What can cause ectopic Wnt signalling?
Ectopic Wnt signalling can occur by loss of APC
50
What can ectopic Wnt signalling cause?
``` Familial adenomatous polyposis Autosomal dominant Many polyps in colon and rectum Occasional loss of remaining APC - Results in activation of Wnt ```
51
What other types of cancer are caused by Wnt?
``` Sporadic colon cancer Breast cancer Ovarian and uterine cancers Melanomas Prostate cancer ```
52
What disease can Wnt cause?
``` Wnt3-tetra-amelia - absence of limbs Bone diseases - LRP5 – gain of function point mutant - Increased bone density - Other LRP5 – loss of function mutations - Decreased bone density Axin2 - tooth agenesis (missing teeth) ```
53
When Wnt and Hh work via alternative pathways what is this called?
Non-canonical signalling
54
What does Shh activate in myocytes/adipocytes?
Activates Smo-Ca Ampk signalling
55
What does Smo-Ca Ampk signalling stimulate?
Stimulates metabolic reprogramming towards aerobic glycolysis - Glucose --> Lactate + 2 ATP - Acidic
56
What do cyclopamine and GDC0449 do?
Certain inhibitors of canonical Hh signaling activate non-canonical AMPK signaling
57
In what other way was the effect of cyclopamine and GDC0449 discovered?
Patients taking hedgehog inhibitors were suffering from serious side effects - weight loss and muscle cramps
58
What impacts the planar cell polarity/convergent extension pathway in vertebrates?
Fz, Dsh, Rho, Rac
59
What impacts the planar cell polarity/convergent extension pathway in zebrafish?
Wnt11 and Wnt5 mutants show defects | - AP axis fails to elongate properly
60
What impacts the planar cell polarity/convergent extension pathway in Drosophila?
Hair on wings

Developmental Biology (16 decks)

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