The role of E-cadherin in mouse embryonic stem cell pluripotency

A problem presented at the UK MMSG Keele 2012.

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Presented by:
Mr Joe Segal (Dentistry, University of Manchester)
Dr Chris Ward (Faculty of Medical and Human Sciences, The University of Manchester)
Participants:
M Albert-Gimeno, MVJ Germain, GE Lang, AC Pratt, SJ Ridden, CH Roney, JM Segal, J Tindall, CM Ward, JP Ward, N Wazula

Problem Description

Our group investigates the role of adhesion molecules in embryonic stem cell (ES) pluripotency, differentiation and tumorigenesis. We have found that the cell adhesion protein E-cadherin plays an important role in regulating pluripotent signalling pathways in mES cells. In addition, E-cadherin repression is associated with ES cell differentiation, which exhibits similarities to tumour cell metastasis.

The principle function of E-cadherin is to maintain epithelial integrity, however, how this process relates to regulation of ES cell pluripotency and molecular processes that define ES cell behaviour and control 'stemness' are not clear. We have shown that expression of E-cadherin is a critical factor in regulating unique signalling pathways in mES cells to maintain pluripotency.

What we hope to obtain through mathematical modelling is initial proof-of-concept of our current data showing the role of E-cadherin in regulating ES cell signalling pathway hierarchy. The contents of these pathways are well studied and should allow mathematical modelling and generation of hypotheses that can be tested in our lab. In the longer term we would wish to determine the exact pathways that E-cadherin regulates in ES cells to allow a better understanding of the role of this protein in ES cell identity.

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Study Group Report

We have developed a nonlinear ODE model of the Activin-Nodal and LIF pathways in embryonic mouse stem cells. The effect of E-cadherin concentration on the expression levels of Nanog have been investigated and our model results have been shown to be in good qualitative agreement with experimental observations.

Our work has elucidated the role of Stat3 phosphorylation in affecting the activation of each pathway — increasing unphosphorylated Stat3 does not remove more Smad4 from the Activin-Nodal pathway and thus downregulate Nanog production. The effect of Nanog inhibition for varying concentrations of E-cadherin has been investigated.

Both these pieces of work have highlighted the need for further investigation of the of inhibitory effects of Stat3-p on Nanog expression levels, both experimentally and in future modelling work.

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