Abstract
BackgroundWe have recently shown that expression of the cell adhesion molecule E-cadherin is required for LIF-dependent pluripotency of mouse embryonic stem (ES) cells.MethodologyIn this study, we have assessed global transcript expression in E-cadherin null (Ecad-/-) ES cells cultured in either the presence or absence of LIF and compared these to the parental cell line wtD3.ResultsWe show that LIF has little effect on the transcript profile of Ecad-/- ES cells, with statistically significant transcript alterations observed only for Sp8 and Stat3. Comparison of Ecad-/- and wtD3 ES cells cultured in LIF demonstrated significant alterations in the transcript profile, with effects not only confined to cell adhesion and motility but also affecting, for example, primary metabolic processes, catabolism and genes associated with apoptosis. Ecad-/- ES cells share similar, although not identical, gene expression profiles to epiblast-derived pluripotent stem cells, suggesting that E-cadherin expression may inhibit inner cell mass to epiblast transition. We further show that Ecad-/- ES cells maintain a functional β-catenin pool that is able to induce β-catenin/TCF-mediated transactivation but, contrary to previous findings, do not display endogenous β-catenin/TCF-mediated transactivation. We conclude that loss of E-cadherin in mouse ES cells leads to significant transcript alterations independently of β-catenin/TCF transactivation.
Highlights
E-cadherin is a member of the classical cadherin family and is expressed on most epithelial cells, including embryonic stem (ES) cells [1,2]
No clustering could differentiate between Ecad-/- ES cells grown in the presence and absence of Leukaemia Inhibitory Factor (LIF) and any variation among these samples can be classified within the normal biological variance
These results suggest that LIF has little or no effect on gene expression profiles of Ecad-/- ES cells despite the LIF receptor and gp130 being localised at the cell surface (KH, unpublished data)
Summary
E-cadherin is a member of the classical cadherin family and is expressed on most epithelial cells, including ES cells [1,2]. The cytoplasmic region of E-cadherin binds to b-catenin, allowing interaction with the actin cytoskeleton via the intermediate protein a-catenin and, most likely, Epithelial Protein Lost In Neoplasm (EPLIN) [8]. P120-catenin binds to the juxta-membrane region of the E-cadherin cytoplasmic domain and contributes to stabilisation of the cadherin-catenin complex by preventing clathrin-mediated endocytosis [9]. Upon Wnt activation, triggered by numerous Wnt proteins interacting with Frizzled receptors, b-catenin degradation is inhibited and the protein is translocated into the nucleus where it interacts with the T-Cell Transcription Factor/Lymphoid Enhancer-binding Factor (TCF/LEF) complex and regulates expression of Wnt target genes. We have recently shown that expression of the cell adhesion molecule E-cadherin is required for LIFdependent pluripotency of mouse embryonic stem (ES) cells
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