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Developmental Biology > L5 - Hh and Wnt Signalling > Flashcards

L5 - Hh and Wnt Signalling Flashcards

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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
Q

If no Hh which two complexes keep Ci out of the nucleus?

A

Costal2 (scaffold protein) and fused serine threonine kinase

Ci and suppressor of fused gene (gene without clear domains)

26
Q

What conditions have to be met for 3 other kinases to act on Ci?

A

The complex costal2 and fused serine threonine kinase has to be bound to Smo

27
Q

What are the 3 kinases that act on Ci?

A

Casein kinase I
Protein kinase A
Glycogen synthase kinase 3 beta

28
Q

The long form transcription factor Ci is?

A

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
Q

The short form transcription factor CiR is?

A

A transcriptional repressor

Hh target genes that are actively repressed

30
Q

What happens to the interaction of Ci with the 3 kinases when a ligand is present?

A

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
Q

How does Hh signalling act on its own pathway in a negative way?

A

Induction of Ptc

Reduced level of Hh activation

32
Q

How does Hh signalling act on its own pathway in a positive way?

A

Induction of Gli1

Gli cannot be proteolyzed into a repressor

33
Q

What is the role of Hh in Drosophila wing patterning?

A

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
Q

What is the role of Hh in vertebrate neural development?

A

Neural tube cells differentiate into different neurons depending on how long and how much Shh
Sources of Hh protein
- Notochord
- Floor plate

35
Q

What is the role of Hh is AP patterning of the limb bud?

A

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
Q

Loss of Hh signalling diseases

A

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
Q

Gain of Hh signalling diseases

A

Basal cell carcinoma
Medulloblastoma
Rhabdomyosarcoma
Inactivation of Ptc1 or Sufu - tumor suppressor genes
Activating mutations of Smo - Smo is a protooncogene

38
Q

Genetic diseases related to Hh

A

Gorlin syndrome
Large numbers of BCCs
Due to heterozygosity for Ptc1 (defective patch)

39
Q

Cancer treatment by Smo inhibitors

A

GDC-0449 - treated patients
Initially good result
But tumor cells acquire resistance by a mutation in Smo

40
Q

Wnt signalling method

A
  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
Q

What is the role of Wnt signalling in Drosophila?

A

Expressed at D/V boundary of wing

Required for patterning and outgrowth

42
Q

What is the role of Wnt signalling in C.elegans?

A

Regulation of neuronal fate leading to migration of two neuroblasts
QRd and QLd

43
Q

What does the small intestine consist of?

A

Crypts and villi

44
Q

What cells occupy the villi?

A

Differentiated enterocytes, enteroendocrine cells and goblet cells

45
Q

What cells occupy bottom of the crypt?

A

Paneth cell

46
Q

What cells occupy higher positions?

A

Stem cell

47
Q

Where is Wnt expressed in crypts and villi?

A

Wnts are expressed by the stroma below the intestinal crypts

48
Q

What happens if you block Wnt signalling in the intestine?

A

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
Q

What can cause ectopic Wnt signalling?

A

Ectopic Wnt signalling can occur by loss of APC

50
Q

What can ectopic Wnt signalling cause?

A 
Familial adenomatous polyposis
Autosomal dominant
Many polyps in colon and rectum
Occasional loss of remaining APC	
- Results in activation of Wnt
51
Q

What other types of cancer are caused by Wnt?

A 
Sporadic colon cancer
Breast cancer
Ovarian and uterine cancers
Melanomas
Prostate cancer
52
Q

What disease can Wnt cause?

A 
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
Q

When Wnt and Hh work via alternative pathways what is this called?

A

Non-canonical signalling

54
Q

What does Shh activate in myocytes/adipocytes?

A

Activates Smo-Ca Ampk signalling

55
Q

What does Smo-Ca Ampk signalling stimulate?

A

Stimulates metabolic reprogramming towards aerobic glycolysis

  • Glucose –> Lactate + 2 ATP
  • Acidic
56
Q

What do cyclopamine and GDC0449 do?

A

Certain inhibitors of canonical Hh signaling activate non-canonical AMPK signaling

57
Q

In what other way was the effect of cyclopamine and GDC0449 discovered?

A

Patients taking hedgehog inhibitors were suffering from serious side effects - weight loss and muscle cramps

58
Q

What impacts the planar cell polarity/convergent extension pathway in vertebrates?

A

Fz, Dsh, Rho, Rac

59
Q

What impacts the planar cell polarity/convergent extension pathway in zebrafish?

A

Wnt11 and Wnt5 mutants show defects

- AP axis fails to elongate properly

60
Q

What impacts the planar cell polarity/convergent extension pathway in Drosophila?

A

Hair on wings

Developmental Biology (16 decks)

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