Development second lecture Flashcards
Describe paracrine signalling
Secretes morphogens to neighbouring cells
Cells further away receive a lower concentration of morphogen
A concentration gradient forms from source to sink
If cells respond differently according to the level of the morphogen different cell fates can be achieved across the gradient
Describe the signals that cause the differentiation of the somites
Wnt signalling from the neural tube and epidermis induces differentiation of the dermatome and the myotome
Dermatome- by neurotrophin 3 and Wnt1 by the neural tube
Myotome- epaxial myoblasts by Wnt1 and Wnt3a
-hypaxial myoblasts by Wnt from the epidermis and BMP4 from the lateral plate mesoderm
What is the significance of Wingless?
It is a morphogen
It exhibits graded distribution of protein and graded responses in surrounding cells
The presence of Wingless prevents epidermal cells from developing denticles; specialised hook structure normally developed in each abdominal segment of the drosophila larvae
In the absence of Wingless the margin is not formed and the wing does not expand
Describe the Wingless signalling pathway
Receptor- Frizzled (+LRP) ➡️Dishevelled➡️-Shaggy(+Apc+Axin)➡️ Armadillo➡️TCF➡️target genes transcribed
(If the pathway is not activated Shaggy will phosphorylate Armadillo which will be degraded by proteosomes
How is the Hunan Wnt pathway different from the drosophila Wingless pathway?
GSK3 instead of Shaggy
Beta-catenin instead of Armadillo
Describe the properties of the receptor in the Wnt signalling pathway
Frizzled in the core receptor- seven-pass transmembrane protein
-probably a G-protein coupled receptor
LRP is a co-receptor for Wnt- stabilises interaction
Describe the properties of the transducer in the Wnt signalling pathway
Beta-catenin is a cytoplasmic-nuclear signalling mediator
Contains a tandem lay repeated 40 as motif that forms a superheli with a positively charged groove that provides an interaction surface with binding partners
Stability is controlled by phosphorylation by GSK3 so it is degraded by a destruction complex including APC-Axin
Describe the control of beta-catenin stability
Axin provides scaffold for the destruction complex
Beta-care in is phodphorylated by casein kinase 1alpha at Ser45
GSK3 successively phosphorylates Thr41, Ser37 and Ser33
Phosphorylated beta-catenin is bound by beta-TRPC (a ubiquitin ligase)
Ubiquitination of beta-catenin targets it for proteosome-dependent degradation
APC regulates the transition from phosphorylation to ubiquitination
How does beta-catenin affect Wnt target genes?
In the absence of Wnt signalling TCF binds a co-repressor Groucho and represses transcription
Binding if beta-catenin to TCF switches it to a transcriptional activator
Give some categories and examples of target genes of Wnt signalling
Cell cycle regulators- C-Myc, Cyclin D1
Tissue specific genes
Tissue remodelling genes- Matrix metalloproteinases, Ephrin receptors and ligands, adhesion molecules
Angiogenesis- VEGF
Give a brief example of Wnt signalling controlling stem cell renewal
Wnt signalling is required to maintain crypt progenitors
Slowly dividing stem cells reside at the bottom of the crypt and generate rapid dividing ‘transit-amplifying’ crypt cells that differentiate into villus cells as they move away from the source of Wnt signalling
What is the significance of Wnt in cancer?
Wnt target genes control cell cycle, structure Nd angiogenesis- components of cancer
Aberrant Wnt signalling leads to cancer eg, familial adenomatous polyposis patients carry one mutant copy of APC
Mutant APC leads to nuclear accumulation of beta-catenin and deregulation of Wnt signalling triggering aberrant proliferation
