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developmental biology > Hh and wnt signalling > Flashcards

Hh and wnt signalling Flashcards

1
Q

give examples of segment polarity genes

A
  • Hh
  • wingless
  • engrailed
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2
Q

creating the Hh signal

A
  1. n terminus signal sequence ensures Hh enters secretory pathway. n terminus is cleaved once it enters the secretory pathway.
  2. c terminus contains a proteolytic domain resulting in autoproteolysis of c terminus
    cholesterol is added to new c terminus end of protein
  3. palmitoylation - palmitate is a fatty acid group
    cholesterol and palmitoyl results in Hh being hydrophobic so Hh is targeted to the membrane
  4. dispatched and scube (in vertebrates only) glycoproteins facillitates Hh release from the cell + long range signalling by loading Hh onto lipoprotein particles
  5. lipoproteins diffuse away from the signalling cell to the receiving cell
    possible use of cytonemes
    HSPGs in the ECM are required for the long range signalling of Hh
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3
Q

creating the Wnt signal

A
  1. n terminus signal sequence is cleaved off when wnt enters secretory pathway
  2. palmatoylation
  3. palmitoleic acid modification
    modifications = hydrophobic –> wnt now insoluble in water and targeted to membrane
  4. wntless involved in membrane targeting/presentation and release of wnt
  5. lipoprotein particles and cytonemes involved in long range signalling of wnt
  6. hspgs in the ECM required for signal to move away from signalling cell
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4
Q

Wntless

A

7 transmembrane protein

involved in membrane targeting, presentation + release of Wnt

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5
Q

what are cytonemes

A

long cellular protrusions that the cell uses to touch other cells and signal to them to change their behaviour

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6
Q

how do cytonemes work

A

signalling molecules accumulate at the tip of the cytoneme

cytoneme moves away from signalling cell and touches neighbouring cell to induce signal in the neighbouring cell

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7
Q

which ortholog of ptch is most important in vertebrates?

A

ptch1

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8
Q

how many transmembrane domains does ptch have

A

12

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9
Q

how many transmembrane domains does smoothened have?

A

7

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10
Q

what is the effect of patched on smoothened in drosophila?

A

patched prevents smoothened from reaching the plasma membrane of the cell

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11
Q

what occurs after hedgehog binds to patched in drosophila?

A
  1. relocation + accumulation of smoothened at plasma membrane
  2. phosphorylation of smoothened
  3. signalling process initiated
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12
Q

what occurs after hedgehog binds to patched in vertebrates?

A
  1. ptch1 removed from cilia
  2. smo accumulates at cilia
  3. signalling process initiated
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13
Q

what is slimb

A

ubiquitin ligase

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14
Q

what is the signalling process that occurs in the absence of hedgehog?

A

2 complexes keeping Ci out of the nucleus:
- fused and costal2 —> bound by 3 kinases = gsk3β, ck1, pka
- sufu
kinases phosphorylate ci
slimb recognises phosphorylated ci –> results in partial proteolysis of ci to form ciR = transcriptional repressor
Hh target genes = repressed

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15
Q

what is the signalling process that occurs in the presence of hedgehog?

A

Ci interaction with kinases CK1, PKA and GSK3β is broken —-> Ci is not phosphorylated by these kinases and is not degraded
Ci is phosphorylated at a different site —–> activator
Fused phosphorylates sufu —> promotes formation of transcriptionally active form of Ci
Hh target genes = activated

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16
Q

what are some developmental diseases resulting from mutated Hh?

A
  • holoprosencephaly (LOF in neural development)
  • polydactyly (webbed digits, GOF in limb formation)
  • syndactyly (webbed digits, GOF in limb formation)
17
Q

what are some cancers resulting from GOF hedgehog signalling?

A
  • Gorlin syndrome - large numbers of basal cell carcinomas
  • medulloblastoma
  • rhabdomyosarcoma
18
Q

What is Gorlin syndrome caused by?

A

heterozygous mutation for ptch1 = tumour suppressor gene

loss of heterozygosity for ptch causes large numbers of skin cancers

19
Q

what are the downstream signalling events occurring in the absence of wnt

A

β-catenin is bound by destruction complex
destruction complex = APC, GSK3β, CKI and Axin
GSK3β and CKI are kinases phosphorylating β-catenin
Slimb recognises phosphorylated β-catenin, ubiquitinates it + targets it to proteasome for degradation

20
Q

what are the downstream signalling events occurring in the presence of wnt

A
  1. wnt binds to frizzled + lrp5/6, bringing the 2 receptors together
  2. dishevelled recruited to frizzled + becomes phosphorylated
  3. destruction complex recruited to membrane. dishevelled binds axin. GSK3β phosphorylates lrp5/6 to create binding sites for axin
  4. b-catenin produced and binds to complex. slimb is lost from complex because destruction complex is bound to plasma membrane
  5. b-catenin phosphorylated but not ubiquitinated by slimb
    so it is not degraded. remains bound to complex as newly formed b-catenin starts accumulating
  6. b-catenin enters nucleus and binds tcf
  7. groucho (transcriptional repressor) displaced from tcf
  8. tcf = activates expression of wnt target genes
21
Q

how is wnt signalling involved in the regulation of neuronal fate in c. elegans?

A

2 neuroblasts = QRd and QLd
wnt signalling in qrd cell induces mab5 —> induces posterior migration
- qrd cells move backwards
- qld cells move forwards

22
Q

what are some diseases associated with mutations in wnt signalling?

A
  • colon cancer e.g. familial adenomatous polyposis
    > loss of apc –> ectopic wnt signalling
    > autosomal dominant
    > loss of heterozygosity for apc —> increased activation of wnt pathway
    > polyps form –> accumulate further mutations + form carcinomas
  • tetra-amelia
  • bone diseases
  • severe tooth agenesis
23
Q

DISEASE: tetra-amelia

A

LOF wnt3a mutation

absence of limbs

24
Q

DISEASE: decreased bone density

A
  • LOF LRP5 point mutation
25
Q

DISEASE: increased bone density

A
  • GOF LRP5 point mutation —> more wnt signal
26
Q

DISEASE: severe tooth agenesis

A
  • missing teeth

- axin2 mutations

27
Q

what is the Warburg effect?

A

aerobic glycolysis as a result of an activated non-canonical wnt pathway
feature of many tumour cells

28
Q

Hh non-canonical pathway

A
  1. shh activates smoothened
  2. increase in intracellular ca2+
  3. activation of ampk
  4. metabolic reprogramming towards aerobic glycolysis
29
Q

what is the effect of shh on myocytes/adipocytes

A

non canonical wnt pathway activated
glycolysis increases lactate production
lactate leaves cells and acidifies extracellular medium
effect = muscle cramps

30
Q

wnt non-canonical pathway and planar cell polarity

A
  1. wnt5/wnt11 bind to frizzled
  2. dishevelled recruited
  3. downstream of dishevelled:
    - celsr
    - prickle
    - inversin
  4. effectors = rho and rac
    polarises cells within sheet
31
Q

wnt non-canonical pathway and convergent extension

A
  • zebrafish
  • axis elongation
    involves wnt11/wnt5

developmental biology (12 decks)

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