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SONIC HEDGEHOG SIGNALLING

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- If you have aberrant expression of Shh, this can lead to polydactyly, i
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the
formation of extra digits
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The Shh signal is synthesised as a precursor, and the c-terminus has a catalytic domain
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The Hedgehog Pathway:
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Germ-line mutations in the gene encoding Patched have been detected in the skin condition
called basal cell nevus syndrome (BCNS), also known as Gorlin syndrome, and is
characterized by BCCs in the skin
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Gorlin syndrome is due to an autosomal dominant or spontaneous hamartomatous skin
condition
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LOH at the PTC locus in skin cells allows these nevi to develop into basal cell carcinomas,
which carry inactivating mutations of the PTCH gene or activating mutations of the SMO
gene
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These means that these cells become ligand-independent, i
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they do not need any Shh
signalling to activate transcription
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BCC and Gorlin syndrome are due to type I ligand independent mutations, whereas, type II
ligand autocrine dependent mutations cause cancers such as lung, pancreatic, breast and
melanomas
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These cancers produce an unusually high amount of one of the Smoothened receptor
ligands, either Indian Hedgehog or Sonic Hedgehog,
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Normally the expression of Pten or p53 prevents the activation of GliA, whereas the
oncogenes Ras and Akt can result in the activation of the hedgehog signalling by allowing
the formation of full-length GliA by preventing its cleavage, leading to proliferation and selfrenewal of cells
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The primary cilium is crucial for hedgehog signalling, whereby the hedgehog signalling
activation is within the cilium
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In the absence of Hh ligand, Ptch1 inhibits Smo activation and ciliary localization
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Smo is phosphorylated by CK1 and GRK2, then assumes an active conformation, and moves
into the primary cilium
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Kif7, Sufu, and Gli also accumulate in the PC, where activated Smo promotes Sufu-Gli
dissociation and activation of Gli (GliA)
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They are characterised by the 9+2 axoneme
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The organelle that is housing or part of the hedgehog signalling network can be lost
due to the defect in the pathway itself
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Notch Signalling & Disease:
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This sequence is important for regulating the stability of the intracellular
domain of the notch receptor
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The notch receptor is secreted as a large precursor and then cleaved in the Golgi
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- Hedgehog can activate components of the notch pathway
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There are modes of signalling & one of them is lateral inhibition
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One cell fate will be surrounded by cells of another cell fate
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This mode is found in neural lineages, gastrointestinal tract
cells and stem cells
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Inductive signalling between boundaries of cells, where one side of the boundary will
receive notch signalling and the other side of cells will not
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Lateral Inhibition:
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Ideally, you
want to have one SOP surrounded by epidermal cells
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Within the vertebrate inner ear, the hair cells upregulate the ligand and they signal to the
surrounding cells which then become the supporting cells
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In an experiment where you induce a gain-of-function NICD, there is no formation of hair
cells and only epithelium is formed, thus demonstrating that this domain is active and
functions to maintain cell fate
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Notch signalling can also maintain stem cells via lineage decisions
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In addition, it can induce proliferation and survival of cells via cyclin D
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Notch Signalling & Cancer:
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Or it can act as a tumour suppressor in skin cancers, where it inhibits proliferation
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This makes the treatment of cancer a little bit more problematic because notch can be
acting as either a tumour promoter or suppressor in different cells
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Notch can be an oncogene, whereby 50% of T-AL patients have activating mutations in the
notch receptor
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In a chromosomal translocation where the truncated notch receptor is placed downstream
of the TCR beta-promoter (T cell receptor), thus causing the activation of the notch signalling
pathway whenever the TCR is activated during the differentiation of T-cells
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In a mouse model, the truncated notch receptor is downstream of the mouse mammary
tumour virus (MMTV), leading to T-ALL development
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In addition to chromosomal translocation, you can also have mutations in other parts of the
receptor which increase the signalling
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For example, you can have a mutation in the heterodimerization domain, which result in the
opening of the receptor complex, making the pathway ligand-independent
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Additionally, you can have signalling in the PEST domain, resulting in the increase in stability
of the intracellular domain by preventing Fbw7 interaction, which allows proteasome
targeting
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These two mutations increase signalling in the pathway – furthermore, these two mutations
co-occur in the same gene
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Fbw7 protein is responsible for degrading the notch receptor and thereby mutations result
in longer lasting notch signalling
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Ikaros is specific for the lymphoid cells and normally inhibits activation of the complex
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à This diagram demonstrates that notch signalling drives the formation of T-cells at the expense of
B-cell formation via inducing proliferation, differentiation and survival and interaction with various
pathways
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In other cells, notch signalling can promote EMT by activating the Twist, Snail, Slug and E-box
TFs
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This results in the formation of mesenchymal cells, allowing the cancer cells to metastasise
to other locations in the body
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In the skin, notch signalling is active in the basal layer where it inhibits p63, Wnt and Shh
signalling pathway, which would normally drive proliferation of the basal cells, thus making
it a tumour suppressor
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g-secretase is one of the enzymes used to cleave the notch receptor and is also important in
the amyloidogenic pathway that leads to beta-amyloid deposition, which is linked to
Alzheimer’s disease
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Problems of using g-secretase inhibitors for Alzheimer’s Disease and cancer is toxicity in the
gut because notch modulates binary decisions in the gut and thus not feasible to use these
inhibitors
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