BIOL211 L19

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  • Created by: Katherine
  • Created on: 19-04-17 11:50
Why is it called the hedgehog gene?
Because it was looking at the dendricles of Drosophila. With a mutation in the hedge hog gene, the drosophia had dendricles all over the ventral side of the body.
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Are Hh found in other species?
Almost every animal have them
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Vertebrates have how many types of hedgehog?
3 = Sonic (Shh), Indian (Ihh) and Desert (Dhh)
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What is Hh?
A secreted signalling protein modified by cleavage and addition of cholesterol
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In the Hh precursor, where does the cleavage occur?
Between Gly-257 and Cys 258
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The sulphur on the Cys258 attacks what?
The N=O bond, generating a thioester
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How does Hh become embedded in cell membranes? What does this do?
Due to the cholesterol - it restricts the activity of the signalling protein
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What is Wg?
Wingless
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It is the job of Hh to..
Induce the expression of Wg in the adjacent cell but only the adjacent cell and no others.
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What does dispatched do?
It releases Hh from the membrane (not cleaved but extracted)
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The extraction of Hh from the membrane allows what?
Allows it to be transported to other cells - because of the cholesterol still attached, it has a tenancy to stick to cell membranes
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Once Hh reaches it's target cells, it must reach a receptor - what is the receptor called?
Patched
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What does patched do?
It inhibits the Hh response (unusual for receptors)
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What does a mutation in Patched result in?
Switched on Hh signalling
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What does Patched interact with?
Smoothened (a 7 pass transmembrane protein
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In the absence of Hedgehog there is...
No expression of target genes
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What is the pathway when Hh is present?
Hh binds to patched. This prevents the inhibitory action on smoothened, so smo can move from intraceullar vesicles to the membrane.
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What happens to smoothened in the plasma membrane?
It's ctoplasmic tail interacts with the cos2 protein. This disrupts the complex, it no longer binds to microtubules, Ci is released from the complex and the proteins are phosphorylated
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Why is it important that Ci is released from the complex?
It is no longer a target for protein kinase A. The full length Ci is able to enter the nucleus and bind to CBP = together they bind to target genes and activates the expression of target genes.
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In the absence of Hh what does patched do to smoothened?
It inhibits it.
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In the absence of Hh which proteins form a complex on microtubules?
Ci, Cos2 and Fu
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In the absence of Hh which protein is phophorylated by PKA?
Ci
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In the absence of Hh what is the result of phosphorlation of Ci?
It is targeted by a proteasome and cleaved into Ci75.
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In the absence of Hh what happens when the 75kDA fragment of Ci enters the nuclues?
It binds to the target gene and inhibits gene expression.
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In the presence of Hh, what is the receptor for Hh?
Patched
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In the presence of Hh, what happens to Smo when Ptc repression is removed?
It moves to the plasma membrane.
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In the presence of Hh, what does the c terminal tail of Smo interact with?
Cos2 and this is linked to Fu
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In the presence of Hh, which two proteins have increased phosphorylation?
Cos2 and Fu
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In the presence of Hh, what happens to the microtubule complex?
It is distrupted and the complex no longer binds to the microtubule. The Ci is released and not phosphorylated.
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In the presence of Hh, what happens to unphosphorylated Ci when it enters the nuclues?
It is full length and binds to CBP, where it then binds to the target gene and acts as a transcrptional activator - activating gene expression
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What is the process of induction of neural fates by Shh (morphogen)
The notochord secretes Shh. Sh induces floor plate. Floor plate secretes Shh. Motoneurons specified at high Shh. V2 interneurones specificed at medium Shh. V1 interneurons specified at low Shh.
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What is the role of Hh is signalling and cancer?
Components of Hh pathwa often mutated in cancers, especially basal cell carcinoma (BCC). Ptc1 is a tumour suppressor (high frequency of BCC in Ptc-/Ptc+ heterozygotes). There is a possibility of anti-cancer drugs based on inhibiors of Hh signalling.
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What is the most common form of skin cancer?
Basal cell carcinoma - occur in high frequency in patients who have Gorlin's syndrom (mutation in Ptc)
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What happens when Ptc is mutated?
You get an excess of hedgehog signalling
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What are Wnt proteins?
Secreted signalling molecules
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What is the Wnt pathway, in the absence of wnt?
GSK3 phosphorylates specific amino acids on b catenin. This leads to b catenin being targeted for ddegregation by proteasome - the who complex is broken down. The phoshorylation is assisted by APC. TCF in nucleus binds to target genes, switching off
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What are the 2 receptors of Wnt?
LRP and Frizzled
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What is the transcription factor in the Wnt pathway?
B catenin
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What is the scaffold protein in the Wnt pathway?
Axin
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In the absence of Wnt, does transcription occur?
No - because the target genes are switched off
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What is the Wnt pathway in the presnece of Wnt?
Wnt binds to Fz and LRP receptors. LRP becomes phosphorylated. It now is a high affinity binding site for Axin. The complex dissociates. B catenin released. It binds to TCF in nucleus. Converts it from repressor to activator of transcription.
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In the absence of Wnt, is LRP phosphorylated or not phosphorylated?
Not
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In the absence of Wnt, what other proteins are held in a complex by Axin?
b Catenin, ACP and GSK3
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In the absence of Wnt, what do CK1 and GSK3 do to B catenin?
They phosphorylate it
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In the absence of Wnt, what happens to phosphorylated B catenin?
It is targeted by proteasomes and broken down.
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In the absence of Wnt, what does TCF do in the nucleus?
It represses gene expression
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In the presence of Wnt, what proteins does Wnt bind to?
LRP and Fz
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In the presence of Wnt, what happens to the LRP cytoplasmic tail?
It is phosphorylated and becomes a high affinity binding site for Axin, meaning that a complex is not held together
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In the presence of Wnt, what is the result of de-stabilisation of the degredation complex?
B catenin is not phosphorylated by GSK3 and therefore is not targeted for degregation by proteasome
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In the presence of Wnt, where does B catenin migrate to?
To the nucleus
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In the presence of Wnt, what happens when b catenin binds to TCF?
It converts TCF from a repressor to a transcriptional activator.
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In the presence of Wnt, what happens to target genes?
Expression is activated
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Why is Wnt signalling essential for the formation of the Nieuwkoop centre?
In b catenin is injected into the ventral side of an embryo, it sets up a second nieuwkoop region to induce an organiser and a second site of gastrulation.
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What can over expression of Wnt signalling do?
Cause cancer. Stimulating division of gut stem cells
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What is APC?
A tumour suppressor - people heterozygous to this develop large numbers of polyps in colon.
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When are mutations which prevent B catenin degregation found?
In colon cancer and melanoma.
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Card 2

Front

Are Hh found in other species?

Back

Almost every animal have them

Card 3

Front

Vertebrates have how many types of hedgehog?

Back

Preview of the front of card 3

Card 4

Front

What is Hh?

Back

Preview of the front of card 4

Card 5

Front

In the Hh precursor, where does the cleavage occur?

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