2016 Group Project 1

From Embryology
2016 Student Projects 
Signalling: 1 Wnt | 2 Notch | 3 FGF Receptor | 4 Hedgehog | 5 T-box | 6 TGF-Beta
2016 Group Project Topic - Signaling in Development

OK you are now in a group, add a topic with your student signature to the group page.

This page is an undergraduate science embryology student project and may contain inaccuracies in either descriptions or acknowledgements.
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  1. The key points relating to the topic that your group allocated are clearly described.
  2. The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.
  3. Content is correctly cited and referenced.
  4. The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.
  5. Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.
  6. Relates the topic and content of the Wiki entry to learning aims of embryology.
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  9. The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic and covered the key areas necessary to inform your peers in their learning.
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Introduction

Topic: WnT Signaling Pathway in skin of fetus

Things to do/ Reference

Friday 9/9/16: 1. Identify all the components of each pathway. (Can possibly look into the similarities vs differences/ interactions between the pathways. 2. Research into how each pathway contributes to fetal devleopment in different body. (Can look into which fetal part we can focus on e.g. skin) 3. Look for picture/diagrams/graphs etc.

Let's get some more information up by next Thursday, 15/9/16

Friday 16/9/16: Good resource: Omim.org (Contains alot of information about different genes and every signalling pathways. How to reference?)

The signalling pathways:

Canonical Pathway - Gloria

    • The Wnt family of secreted glycolipoproteins play an important role in the role of embryonic development and adult homeostasis.
    • They do so via the transcription of β-catenin, which accumulates in the cytoplasm and eventually gets translocated into the nucleus to act as a transcriptional coactivator of transcription factors that belong to the TCF/LEF family.
    • The canonical Wnt pathway of (Wnt/ β-catenin pathway) is the Wnt pathway that causes β-catenin to stay in the cytoplasm rather than be degraded through ubiquitination which is induced by destruction complexes. The destruction complexes which sends β-catenin to proteasome for digestion are proteins such as: Axin, adenomatosis, polyposiscoli (APC), protein phosphatase 2A (PP2A), glycogen synthase kinase 3 (GSK3) and casein kinase 1α (CK1α).
    • Once the stabilised β-catenin enters the cell nucleus it acts as a transcriptional coactivator for transcription of Wnt-target genes. The primary family of transcription factor which β-catenin associates with is the TCF/LEF family. Activation through β-catenin is mediated with compounds such as histone acetyl transferase CBP, the chromatin-remodeling SWI/SNF complex and Bcl9 bound to pygopus (Pyg).
    • This signalling pathway is crucial for deciding the fate of cells during early embryogenesis.


<pubmed>19279717 </pubmed>

Canonical Pathway: How it works - Gloria
    • Wnt family of signalling proteins plays various roles in fetus development of embryogenesis.
    • Wnt signals are pleiotropic (when a gene has effects on two or more seemingly unrelated phenotypic traits). The signals have effects on mitogenic stimulation, cell fate specification and differentiation.
    • In the canonical pathway, Wnt ligands bind to frizzle receptors that are at the cell surface.
    • Due to this activation of Wnt signalling, B-catenin, which is normally degraded within the cell, starts to accumulate in the cell and ultimately the nucleus.
    • At normal levels of B-catenin, the protein binds at the intracellular side of the membrane with cadherins to promote cell adhesion and also controls cell shape through actin microfilament cytoskeletal network.
    • However at elevated level of this protein, activation of transcription occurs alongside co-transcription factors such as action of Lefs/Tcfs.

<pubmed>15473860 </pubmed>

Canonical Pathway & Embryogenesis - Gloria

Non-Canonical Pathway - Caroline

    • The non-canonical pathway can also be referred to as the beta-catenin independent pathway, due to the absence of β-Catenin.
    • The non-canonical pathway can be divided into two pathways known as the Planar Call Polarity pathway or the PCP pathway.
    • The PCP pathway was discovered through genetic studies in Drosophila. It was found that mutations in Wnt signaling resulted in a randomised orientation of epithelial structures.
    • During vertebrate gastrulation, the mesodermal and ectodermal cells undergo convergent extension. Polarized cells will thus intercalate along the mediolateral axis, resulting in mediolateral narrowing (convergent) and anteroposterior elongation (extension).
    • The non-canonical Wnt pathway regulates cell polarity and movements of dorsal mesodermal cells during convergent extension and later during neural tube closure.
    • Studies suggest that the non-canonical pathway has an impact on the expression of early cardiac genes. The non-canonical pathway affects the histone deacetylase (HDAC) activity, which in turn is affected by CaMKII, which is necessary for the expression of the cardiac genes. Thus, any discrepancy in the non-canonical pathway would result in a discrepancy in the normal cardiac development


<pubmed>19279717</pubmed>

<pubmed>27101101</pubmed>

<pubmed>26989192 </pubmed>

<pubmed>26680417</pubmed>

<pubmed>26555387 </pubmed>

<pubmed> 26499793</pubmed>

<pubmed> 26035863</pubmed>

<pubmed> 25732825</pubmed>

<pubmed> 25428587</pubmed>

<pubmed> 25448697 </pubmed>

<pubmed> 25540130</pubmed>

<pubmed> 25410658</pubmed>

<pubmed> 25266145</pubmed>

WnT-Calcium Ion Pathway - Tony

Wnt-Calcium Ion Pathway has generally been accepted as a non-cononical wnt signalling pathway using Calcium ions as secondary messengers. It main function is thought to antagonist the canonical wnt signalling pathway by decreasing the cellular beta-catenin concentration. Wnt-4, -5a & -11 were identified as ligands specifically activate this pathway. Wnt (5a) interact with Fz receptor. Fz receptor functions as a G-protein coupled receptor which activates Gaq/11. Gaq/11 further cleaves PIP2 into DAG and IP3. IP3 then interacts with the IP3R on the surface of endoplasmic reticulum and causes increase in intracellular calcium ions. Those calcium ions will then react with CAMKII or calcineurin leading to further internal effects. DAG and calcium ions are also able to activate proteins belongs to PKC family which also posses various cellular effects.

  • Ca/CamKII pathway.
    • Main components
      • Calcium/calmodulin-dependent kinase II (CamKII)
      • PKC
    • Functions
    • Abnormalities
  • GTP-binding protein pathway
    • Main components
      • Heterotrimeric GTP-binding protein
      • Phospholipase C (PLC)
      • Phosphodiesterase E (PDE)
    • Functions
    • Abnormalities
  • PCP pathway
    • Main Components
      • Planar cell polarity
      • Jun-N-terminal Kinase (JNK)
      • Small GTP-binding proteins
    • Functions
    • Abnormalities
  • PMID 26956615
    • In this article, several in vitro experiments using mouse ESCs, NC cells and mesenchymal stem cells were performed. Wnt5a was reported to posses an osteogenic effect when the induction was done before 7 days of incubation. Several osteoprogenitor markers such as Alp, Opn, Ocn and Bsp were found to have an elevated mRNA expression level, while expression of chondrocyte-specific markers such as Agg and Col2a1 were down regulated. Moreover, EMT markers Snai 1&2 were also found to be increased in the induced cells. Downstream targets of wnt5a (CamkII-alpha, Jnk 1&2 and PKC) were reported to be upregulated at the mRNA level and their activities were also found to be increased. Furthermore, activation of wnt-calcium pathway has also been suggested to decrease the nuclease beta-catenin level and its inhibition may restore the beta-catenin level. However, when the wnt5a induction was performed after day 7, the expression of osteoprogenitor markers were not related with wnt5a. Instead, they were now upregulated by the induction of wnt3a, which activates the caniconical wnt-signalling pathway. Endogenous expression of wnt3a was also increased in the same cells. Interestingly, similar changes were not observed in mouse NC cells or mesenchymal stem cells, indicating this character might be ESC only. It is suggested that wnt-calcium pathway may antagonist the effect of caniconal wnt pathway. There is significant cross talk between those two pathways, and their effects may varies depending on the cell period and cell type.
  • PMID 21903638
    • WNT5 ligands were specifically studied since calcium ions are secondary signaling molecules of wnt5. During gastrulation, wnt/beta-catenin pathway is switched on to promote migration of cells, while wnt/calcium pathway is later turned on to stop its effect. Wnt signalling pathway is especially important in guiding the movement of embryonic cells, and wnt/calcium pathway is especially active during gastrulation process.
    • Drosophila and zebrafish models are frequently used to study wnt singalling pathway, due to the fact that wnt signaling is quite conserved across species.
    • Wnt/calcium pathway has also been know to be able to alter the signalling transduction of wnt ligand through other receptors.
  • PMID 17881570
    • It is suggested that wnt3a is identified as a wnt canonical pathway ligand in hematopoietic stem cells. However, wnt5a functions in the same cell line mainly as a wnt canonical pathway antagonist since the intracellular catenin level was significantly decreased. Wnt 5a is able to increase the transcription of BCL-2 in the HSC cells and therefore, increase their life span. It seems that in HSCs, wnt5a can also induce the transcription of hes-1 gene which then activates Notch signalling pathway. Notch signalling pathway has been reported to be able to increase the re-productivity of the HSCs. Therefore, it can be seen that wnt5a also possesses a positive effect on HSCs reproduction. wnt5a induces the self-renewal of HSCs, while wnt3a induction increases the amount of c-myc whcih inhibits this action.

How does it work in a foetus (skin formation) - Arsalan

Wnt signalling is an important component of skin formation in the very early stages of foetus development. Once the embryo undergoes gastrulation, cells of the ectoderm will form differentiate to form the epidermis and the mesoderm will form the dermis.

WnT signalling strongly influences the decision of the ectoderm layer specifying as nervous system or skin epithelium. WnT signalling inhibits the ectoderm’s responsiveness to the fibroblast growth factors. This inhibition is essential for the ectodermal cells to be able to express bone morphogenetic proteins that result in blocking neural induction and directing the cells to differentiate into keratin expressing cells that form the epidermis.

In terms of the mesoderm WnT signals are important for the process of somitogenesis, in which the mesoderm segments into somites that eventually form the dermis. WnT signals will also instruct the lateral plate mesoderm and somite derived cells to create mesenchymal cells which are essential cells within the dermis.

<pubmed>PMC3552514</pubmed>

===What can go wrong?=== z341763

Cells need to communicate with each other so they can act in a coordinated manner in response to the environment. Communication occurs through signalling pathways which, stimulate, inhibit and coordinate the behaviour of cells to grow or divide during the appropriate times. This can hence become a very pedantic and intricate process and little changes can interrupt the entire system. When things go wrong in signalling, cancer can happen.

In most normal cells the Wnt pathway is inactive and the beta catenin is destroyed and gene transcription is inhibited. In tumour cells, the Wnt pathway may be activated despite the absence of a Wnt signal. This is a result of a mutation of a gene that carries code for a protein complex and hence disintegrates the protein complex. The beta catenin is now no longer tagged for destruction and its cellular level continues to increase. This is very similar to a normal cell where the pathway was actually activated by the Wnt Signal. Beta catenin reaches the nucleus and activates the TCF and LEF transcription factors which activates an RNA polymerase and transcription of several genes begin. This however is inappropriate and uncontrolled and hence leads to cancer. One of the most common mutations is the mutation of the APC protein and is directly linked with the development of colon cancer. People who inherit defective APC alleles’ develop large numbers of polyps which become malignant adenocarcinoma(insertfootnote). People who have mutant APC have nearly a 100% chance of developing colon cancer by the age of 40 years.

Reference(im not sure how to reference things that arent from pubmed) http://www.cell.com/cell/fulltext/S0092-8674(06)01344-4 Wnt/β-Catenin Signaling in Development and Disease Clevers, Hans Cell , Volume 127 , Issue 3 , 469 - 480

References

PMID 21903638

Glossary